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Pathophysiology: ID & Micro

Introduction to Infectious Diseases ........................................................................................................................................ 2

Prokaryotic Structure & Physiology ........................................................................................................................................ 5
Bacterial Toxins ....................................................................................................................................................................... 9
Fever & Sepsis ....................................................................................................................................................................... 12
Diarrheal Disease Caused by Bacteria................................................................................................................................... 15
Staphylococci ........................................................................................................................................................................ 22
Prion Disease......................................................................................................................................................................... 25
Academy Awards of Infectious Diseases .............................................................................................................................. 27
Anaerobic Infections ............................................................................................................................................................. 28
Chlamydia & Mycoplasma .................................................................................................................................................... 30
Non-Tuberculous Mycobacteria (NTM) & Nocardia ............................................................................................................. 32
Antimicrobial Stewardship .................................................................................................................................................... 36
Syphilis (& other STIs) ........................................................................................................................................................... 39

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

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

Probability of disease equation:

inoculum size × growth rate × virulence

𝑷𝒅𝒊𝒔𝒆𝒂𝒔𝒆 =
host resistance

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
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
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 Complement: series of plasma proteins, cell receptors that mediate inflammation

 Liver produces complement (starvation: protein ↓, complement ↓)
 Most important effects: activated C3 and C5-9
 Pathways:
 Classical pathway (Ag-Ab complexes)
 Alternative pathway (polysaccharides via C3)
 Lectin-binding pathway
 Mechanisms of action:
 opsonization (C3b) – increase attachment & phagocytosis (Mφ & PMN)
 chemotaxis (C5a) - attracts PMNs
 cell destruction (membrane attack complex)

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

o Interferons: cytokine (glycoprotein) cell-signaling molecules produced by

immune system cells in response to challenge (immunuloregulatory Responses to infection
signals) (will discuss in detail later)
 Interferon α – “leukocyte”interferon; from all cells in response to  Fever
viral infection or dsRNA, upregulate MHC class I  Anorexia
 Interferon β – “fibroblast”interferon; from all cells in response to  Lethargy
viral infection or dsRNA, upregulate MHC class I  Myalgia
 Interferon γ - “immune” interferon, from T-cells in response to
antigen/mitogen, upregulate macrophages & MHC classes I & II

 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

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
 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

 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)

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 (+) )

 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

Structural differences: Gram Positives vs Gram Negatives

Cell membrane in prokaryotes:

 no sterols (unlike eukaryotes)
 Important: active transport, energy generation, cell wall precursor synthesis, secretion of enzymes/toxins
Gram Positive Gram Negative
1. Phospholipid cell membrane, then 1. Inner phospholipid membrane, then a
2. large peptidoglycan layer anchored to cell 2. small peptidoglycan layer in the periplasmic space, covered by
membrane by lipoteichoic acids (LTA) 3. outer phospholipid membrane with lipopolysaccharide (LPS)

Important features of bacterial cell walls:

Teichoic Acids: (Gram + only)

 antigenic (glycerol or ribitol phosphate)
 anchor to cytoplasmic membrane or NAM of peptidoglycan
 useful for anchoring cell wall & adherence to cell membrane

Peptidoglycan (Gram + and -, but more & more exposed in Gram +)

 Cross linked chains of monomers (NAG-NAM pentapeptide)
 Transglycosidase enzymes join monomers to make chains
 Transpeptidase enzymes make peptide cross-links between
chains (strength & enable bacterium to resist lysis)
o Penicillin blocks this transpeptidase
o Note the peptide side chains coming out at right angle

Gram + (A) and Gram - (B) Cell Walls

Lipopolysaccharide (LPS): (Gram – only)

 Lipid A: “endotoxin”
o Conserved among Gram (-)
o Highly immunostimulatory
o Causes unforgettable sepsis
o Made of sugars & fatty acids
 Core polysaccharide somewhat conserved among species
 O-specific polysaccharide different even within species

Gram Negative Sepsis

 Gram (-) sepsis is really bad – death not due to organism but rather immune system going crazy
 Tx: give fluid (will accumulate in extremities after leaking out: puffy appearance)
 Short-term Tx: Abx expose lipid A, cause worse short-term consequences
o Why can’t we get mortality in gram (-) sepsis to 0% (around 30% for years)?
o Maybe because Abx precipitate some LPS/Lipid A release & toxicity results
 Lipid A is key player: actions include
o Febrile response
o Activation of complement, granulocytes, macrophages
o ↑ interferon production
o ↑TNF (↓ capillary endothelial cell permeability; development of shock)
o ↑ colony-stimulating-factor production
o B-cell mitogen

Bacterial capsule:
 Gelatinous layer, covers bacterium, found in some spp, usually polysaccharide
o Sugars vary spp to spp; can use to do serological typing
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

Bacterial division (Binary Fission)

 1 parent cell  2 identical progeny cells
 Exponential growth (2n where n = # generations)
 Doubling time: 20 minutes to days

Bacterial growth cycle

1. Lag phase: get used to environment, get ready to
start dividing (A)
2. Log growth phase (C)
3. Run out of space & food; equal # die & divide (E)
4. No more food, etc. death (F)

NB: Many Abx work best in log growth phase

Aerobic & Anaerobic Growth

Using oxygen generates two toxic molecules: H2O2 and O2•
(superoxide). Bacteria need two enzymes to use oxygen.
1. Superoxide dismutase (2 O2• + 2 H+  H2O2 + O2)
2. Catalase (2 H2O2  2 H2O + O2)

 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

Transfer of DNA within bacterial cells

 Transposons: DNA from one site on chromosome to another site or to plasmid. Can lead to antimicrobial drug
 Programmed reagrangements: movement of gene from silent site to site where it’s transcribed & translated.
Can lead to antigenic variation

 These are two ways that inducible resistance can arise, or production of a toxin which wasn’t previously
produced, for example.

Transfer of DNA between bacterial cells

 Conjugation: mating of bacterial cells, DNA transferred via sex pilus, etc.
 Transduction: transfer of genetic material via a bacteriophage (bacterial virus)
 Transformation: transfer of DNA (extracellular) itself from one cell to another

Bacteria & Iron

 All organisms need exogenous iron source; free-living bacteria commonly use siderophores to chelate iron from
environment for their use
 Human host: iron not found in unbound form (maybe a way to control bacterial growth?). Instead bound to
proteins (transferring, lactoferrin, ferritin, myoglobin, hemoglobin, etc.)
 How do bacteria get iron?
o Produce special siderophores (compete with iron-binding proteins)
o Direct uptake by stealing from tranferrin / lactoferrin
o Use of heme from breakdown of tissues
 Clinical importance: host sequestration
o chronic infections can lead to anemia
o not iron-deficiency anemia – instead, host tries to hold onto iron more
o iron stores are actually increased in the red cells that are present).

Bacterial Toxins
Toxins: molecules produced by microbes that can produce disease
Toxoids: detoxified toxins that retain antigenicity / immunogenicity)  vaccinations (diphtheria, tetanus)

Categorization: chemical composition (protein/lipid/LPS), cell/tissue target (enterotoxin/neurotoxin), mechanism of

action (proteolytic/adenylate cyclase toxin) biologic effect(lethal factor / edema factor), organism (pertussis toxin,
cholera toxin), intracellular target, specificity (broad/targeted)

 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

Toxin genes:
 chromosomes (cholera),  bacteriophage (diphtheria),
 plasmids (E. coli heat-labile),  combination (Staph enterotoxin)

Control & regulation of exotoxin synthesis & release:

 Diptheria toxin: production↓when iron around; Cholera toxin / virulence factors: environmental osmolarity, temperature
 Toxin often required for virulence & pathogenicity
 Distinct pathways for secretion; details have significant impact on toxin/pathogen virulence
o Direct injection, series of pores, assembly in periplasmic space, etc.

Structure: A-B toxins

 Most exotoxins: A (active, enzymatic  toxin effects) and B (binding) domains
 Need both for effects to be exerted on cells (binding & activity)
 Permutations: A:5B, A-B, A+B, etc.
 Attachment & entry: direct entry (B-subunit  pore formation), receptor-mediated endocytosis, both

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

Attatchment & entry: different types

 Non-selective (e.g. cholera toxin) so clinical manifestation is from localization of organisms / toxin
 Coupling between toxin-receptor complex; lipid rafts in host cell plasma membrane (anthrax LF/EF)
 Some could act against most cells, but only can bind to certain surface receptors on certain cells (pertussis)
 2 toxins may catalyze the same intracellular reaction (e.g. diphtheria toxin, pseudomonas exotoxin A) but have
different clinical manifestations (different receptors, different cell distributions)

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.

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).

Produces three toxin components (need all 3 together)

 A: Edema factor (EF): an adenylate cyclase (↑cAMP in phagocytes, forms ion-permeable pores). Edema,
phagocytosis inhibition, impaired host defenses.
 A: Lethal factor (LF): a protease (cytokine release, cytotoxicity: lysis of Mφ, ↓PMN activity)
 B: Protective antigen. Binds glycoprotein receptor; cleaved by host protease, then binds EF or LF; complex
endocytosed, increased cAMP.

Diptheria: uncommon (universal vaccination with diphtheria toxoid); endemic in Latin America / Carribean, immunity
does not prevent carriage, adult immunity wanes without booster.

Diphtheria toxin: produced as single polypeptide; cleaved by trypsin

 A: catalytic domain
 B: binding domain (receptor for cell attachment)
 T: hydrophobic domain (insertion into endosome membrane, secure A release)
 Process: B binds, RME  endosome; acidification  unfolding of A&B to expose T  T inserts into endosome 
A translocated to cytoplasm  enzymatic activity (ADP-ribosylates)
 Causes systemic toxicity proportional to the burden of pharyngeal exudates
 Most severe manifestations:
o Cardiac toxicity (myocarditis): arrhythmia, can lead to heart failure & hemodynamic collapse
o Neurotoxicity: cranial neuropathies, paralysis of pharyngeal wall / soft palate, delayed peripheral

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,
 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:

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

Summary: Endotoxin vs. Exotoxin

Chemical nature Lipopolysaccharide Protein
Relationship to cell Part of outer membrane Extracellular, diffusible
Antigenic Yes Yes
Form toxoid No Yes
Potency Relatively low Relatively high
Enzymatic activity No Often
Pyrogenicity Yes Occasionally

Biological activities: overstimulation of immune system, pyrogenicity, shock
 Superantigen mediates non-specific interaction between class II MHC on APCs and specific Vβ chains of TCR on
 Massive stimulation of T-cells (20% activated  massive cytokine release)
 Toxic shock syndrome: Hypotension, fever, diffuse erythematous rash

Examples: pyrogenic exotoxins of Group A strep and Staph enterotoxins

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

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)

 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
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


 Closely regulated, purposeful response (evolved)  Basal metabolic rate ↑10% for 1°C rise in temp
 Stimulates the immune response  3rd world countries: chronic infection & fever in children;
 1°C rise in temp = 10x the stimulatory effect of IL-1 on T- food supply already marginal, metabolic needs can’t be
cells  more B-cell activity, more Mφ activity, more met, promotes more infection (cycle)
cytotoxic lymphocyte output  Hospitals: gross malnutrition common in chronically
 Most organisms have growth optima ~ 37C (want to infected adults; don’t heal surgical wounds, ↑risk more
make environment inhospitable) infections

 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)

Acute-phase response (APR):

 various physiological reactions mediated by same group of pyrogenic cytokines that activate the thermal
response of fever (mostly IL-6)

 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

 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)

Syndrome of injury to small vessels

1. Mφ secrete cytokines (TNF, IL-1,etc.) producing inflammation in capillaries all over body
a. Endothelial cells lose contact with each other; express proteins to bind PMNs
b. Secretion of:
i. Prostaglandins (vasodilation, low BP, vascular permeability ↑)
ii. Leukotrines (permeability ↑)
iii. Thromboxanes
iv. Platelet activating factor (↓BP, ↑aggregation)
v. Nitric oxide (vasodilation) Clinical Features of Sepsis
2. Vessels: dilated & leaky (obstruction of vessels / plugs of platelets &  High cardiac output
PMN)  Low systemic vascular resistance
a. Lightly bound PMN: emigrate into tissue, cause damage there  Tachycardia
b. Tightly bound PMN: degranulate directly onto vessel walls  A-V shunting with poor tissue
c. Vessel walls destroyed: lipid peroxidation, proteolysis, extraction of O2
induction of apoptosis  Acidosis / elevated blood lactate
d. ↑ thrombin production, ↑ clotting  Increased gut permeability
3. Blood shunted around tissues, fluid & protein lost from blood, tissues
waterlogged, tissue ischemia DDx: conditions where BP decreases
4. Organ dysfunction:  MI, bleeding: SVR↑, CO↓
a. Lungs fill with fluid, oxygen uptake fails (further ischemia)  Sepsis: SVR↓, CO↑ (HR↑)
b. Heart: acidotic, ischemic: fails
Clinical problems:  support vital functions (FLUIDS) &
 Antibiotics can control infection oxygenation if needed
 hope for the best
 Fluid infusions restore volume & BP, but fluid doesn’t stay intravascular (tissue edema gets worse)
 Ventilator support: restores oxygenation temporarily but can damage lungs (O2 toxicity, high pressures)
 Often survive a few days, then die of progressive multi-organ failure (MOF)

Role of activated Protein C (not CRP)

 Activated by thrombin bound to thrombomodulin
 Normally inhibits clotting cascade (↓thrombosis, ↑fibinolysis)
 Body runs out of protein C during sepsis
 Protein C levels predict mortality
 Replete protein C as Tx (inhibit thrombosis, promote fibrinolysis): cut mortality from 30% to 25%
o (other interventions post-antibiotics didn’t affect long-term mortality)

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)

Diarrhea defined by frequency, consistency, volume, change from normal habits

 Acute: Secretory (mostly viral & bacterial) or invasive (mostly bacterial)
 Chronic (2-3wks+): mostly parasitic, less commonly bacterial; can be non-infectious (eg. inflammatory bowel dz)
 Traveler’s diarrhea: mostly bacterial, reflecting organisms that cause diarrhea in local children

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

Pathophys: Mechanisms for Diarrhea

1. Decreased absorption
a. inhibited/defective absorption from villous cells Oral vaccines for diarrheal dz prevention
b. luminal presence of osmotically active agents  Typhoid
c. decreased contact time (rapid transit time)  Cholera
2. Increased secretion  ETEC, Shigella, Campylobacter in
a. Stimulated anion secretion from crypt cells development

Bacterial agents of acute diarrhea: mostly Gram (-) rods

 E. coli: Enterotoxigenic (ETEC), Enteropathogenic (EPEC),
Enterohemorrhagic (EHEC)
 Vibrio: V. cholerae O1 & O139, V. parahemolyticus, V. vulnificus
 Shigella: S. dysenteriae, S. flexneri, S. sonnei, S. boydii
 Salmonella: Salmonella (non-typhoid), S. typhi
 Campylobacter jejuni
 Yersinia entercolitica
 Anaerobes: C. difficile, C. perfringens, B. fragilis (enterotoxigenic
 Others: aeromonas, plesiomonas, L. monocytogenes, more

Fecal-oral transmission
 Developing countries: contaminated water supply, inadequate latrines, poor sanitation
 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

 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+

Secretory Diarrhea: Vibrios & ETEC

Both Gram (-) rods

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
 ↓ 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)

Diagnosis: difficult, need special media (TCBS agar)

Treatment: Abx usually NOT required (self-limiting; 2-3d)

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

Invasive diarrheas: Shigella & more

Shigella (prototype of invasive diarrhea): Gram (-), non-spore-forming rod
 Low inoculum size (101-2): person-person spread is usual The 4 Shigellas
 Pass through small bowel  invade large bowel; move laterally causing  S. dystereria (Shiga bacillis) =
cell death. most severe
o inflammatory changes of mucosa (huge changes on histology  S. flexneri: most prevalent in
o diarrhea with blood & pus developing countries
o fever & abdominal pain  S. sonnei: most prevalent in
 Dx: stool culture (non-lactose fermenting, non-pigmented colonies) developed countries &
 Tx: antimicrobials. Increasing resistance in developing countries travelers to developing
o Cipro when resistance is high countries
o Loss of fluid isn’t huge, but ORS can be used when necessary  S. boydii: relatively uncomon

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

Clinical presentation: invasive diarrhea, much like Shigella

 Stool: pus, RBC
 Fever, abdominal pain; can be Asx in yong children in tropics
 Association with Guillain-Barré syndrome (autoimmune, ascending paralysis): serotype O19 may have
immunologic cross-rxns with GM1 ganglioside in nerve tissue

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

Enterohemorrhagic E. coli (EHEC)

Gram (-) rod
 Most common E. coli in USA
 Can cause bloody diarrhea with possible life-threatening sequelae: hemolytic uremic syndrome (HUS)

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!) 

 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

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)

Dx: stool culture, blood culture if bacteremia suspected

Tx: Abx optional for mild cases, essential in severe cases. Fluoroquinolones/ceftriaxone/cipro

Typhoid Fever (S. enterica, serotype typhi)

Gram (-), non-lactose fermenting rod, single clone worldwide
 Only infect humans (chronic carriers important: food handlers, etc.)
o Chronic carriers: ID via stool cultures, Ab to Vi antigen
 Can treat with prolonged Abx, may require removal of gall bladder (previously more common)

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

Fecal-oral transmission (from chronic carriers); carried primarily in gall bladder

 Requires high inoculum size (104-7)

Pathogenesis: Incubation: 7-14 days

 Invade small intestine through M-cells (in Peyer’s patches, take up antigens & present to T-cells)
 Transported to lymphatics  blood stream  all parts of body
 Persist in mononuclear cells

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)

Dx: cultures: blood, bone marrow, stool, duodenal fluid

 (string test: swallow string to obtain sample of upper small intestine)
 Some serological tests but not diagnostic acutely

 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

Risk factors: use of broad-spectrum Abx, intestinal surgery, age

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

Prevention: infection control procedures; controlling use of antimicrobials

 Doxycycline, macrolides, aminoglycosides, fuloroquinolones less likely to result in C.diff overgrowth
 Isolation, use disposable materials, careful hand washing
 Bacterial spores survive on inanimate objects (wash & decontaminate hospital rooms)

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)

 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)

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

Reservoir: environment, animals (especially pigs)

 Grows at refrigerator temperature (fairly unique for food-borne); found in most colder temperate areas
(Canada, not tropics)
Transmission: ingesting contaminated foods (raw milk, contaminated water, pig tongues)

Clinical presentation:
 self-limited, mild gastroenteritis;
 can provoke mesenteric adenitis which can present as “pseudo-appendicitis”

Dx: culture of stool, blood

Tx: not needed except in severe cases (gentamicin, fluoroquinolones used)
 Avoid unnecessary surgery
Prevention: avoid undercooked meat (e.g. pigs) & unpasteurized milk

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

Dx: serology or hydrogen breath test

Tx: combination of 2+ antibiotics and proton pump inhibitor to reduce gastric acid; reinfection is common

Organisms not covered in this lecture

 Clostridium perfringens: anaerobic Gram (+) spore-forming rod; normal inhabitants of GI tract; produce lots of
toxins, responsible for multiple diarrheal diseases (enteritis necroticans) & “Pig Bel”
 Bacteroides fragiles: anaerobic Gram(-) rod; produces enterotoxin; responsible for mild diarrhea (developed &
developing countries)
 Enteroadherent E. coli (EAEC): diarrheal dz in children (developing & developed countries); relatively common
cause of traveler’s diarrhea
 Enteroinvasive E. coli (EIEC): dz resembles shigellosis; closely related to Shigella spp.

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

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
 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!)

Coagulase negative Staphylococci

Examples: S. epidermidis, et al.
 No virulent exotoxins
 Form biofilms (secreted polymeric carbohydrate gel; surrounds micro-colonies of bacteria)
o Acts like capsule (keeps out Ab, C’, PMN, Abx)
o Adheres to plastic (catheters, pacemakers!) Rule of thumb: less virulent =
o Hard to eradicate more abx resistant

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

Epidemiology: pretty much everyone infected between birth & death

 NOSE, skin/appendages (hair follicles, sweat glands), GI tract, vagina common colonization sites
 Minor skin infections: pretty much everybody (intact immunity prevents spread)
 Major disease: immunosuppressed; normal people after initial insult (wound/injury, IV drugs, influenza)

Virulence factors most associated with S. aureus:

 Surface proteins
o Protein A: binds Fc of Ab; exposes Fab to phagocytes (don’t recognize; so antiphagocytic)
o Coagulase: binds prothrombin; forms staphylothrombin, which catelyzes fibrinogen  fibrin
o A & B clumping factors: bind fibrinogen, with coagulase lead to localized clotting (other spp mostly)
 Why promote clotting? Wall off from immune system & response; leads to ischemic injury
 Toxins
o Exoenzymes (proteases, lipases, allow spread through tissues)
o Hemolysins (4 types; lyse RBC & other eukaryotic cells)
o Leucocidins: e.g. Panton-Valentine Leukoidin, pore-forming hemolysin; results in degranulation/lysis of
PMNs, associated with aggressive infections (furunculosis, necrotizing pneumonia)
o Superantigens: stimulate T-cells nonspecifically (cytokine release, clinical shock)
 Enterotoxins (food poisoning), exfolatins (scalded skin syndrome), TSST-1 (toxic-shock-syndrome

Transmission: person-person (direct or indirect: intermediary

person’s hands)
 Hospitals: patient-patient or via healthcare worker’s
 Community-based: household contact
 Environmental surfaces commonly contaminated (role in
MRSA spread controversial)

Immunity: conditions with increased susceptibility

 PMNS are primary defense against S. aureus
 Deficient neutrophil number
o Congenital: congenital neutropenia; bone marrow aplasia/failure
o Acquired: leukemia, chemotherapy
 Defective neutrophil function
o Chronic granulomatous disease (CGD): defect in oxidative burst, still opsonize/internalize
 Path: see PMNs packed with bacteria (chronic infection; can’t kill)
o Leukocyte adhesion deficiency (LAD): make normal PMNs but can’t extravasate
 Path: see tons of bacteria, no PMNs in infected area
o Chediak Higashi syndrome (# & function), Hyper immunoglobin E syndrome (Job’s syndrome)

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
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!

 MRSA: Methacillin-resistant S. aureus

o Chromosomal (mecA): on a mobile genetic element (SCCmec, staphylococcal cassette chromosome)
o Results in resistance to all beta-lactam antibiotics (includes cephalosporins)
o 2 types of MRSA: different SCCmec types, different abx resistance genes/toxins

 Hospital-acquired MRSA (HA-MRSA)- “USA 100-200”

 Hosp. pts, often very old/young, major illness, surgical incisions, IV cath, trach tubes,
dialysis, etc.; more likely to have implanted foreign bodies
 Handled frequently & all over by other people
 2008: 60% HA-S. aureus = MRSA!
 Multidrug resistant (type I,II,III SCCmec); no PVL

 Community-acquired MRSA (CA-MRSA) - “USA 300-400”

 Up to 75% SSTI now CA-MRSA in most areas of country
 Now also causing hospital outbreaks/infections
 Nosocomialcommunitynosocomial
 Not multidrug resistant (type IV SCCmec); produces PVL (cytolytic toxin)
 CA-MRSA (PVL-producing) clinical manifestations
o Skin infections (Children, athletes, prisons, previously healthy persons)
o CA-pneumonia (esp. after influenza; necrotizing; associated bone infection,
thrombi; unusually severe/high mortality, previously healthy persons!)

 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?

Prion Disease
Prion: a proteinaceous infectious particle which is resistant to inactivation by most procedures that modify nucleic acids

Transmissible spongiform encephalopathies: Prion Diseases

 Animals:
1. Scrapie (sheep)
2. Bovine spongiform encephalopathy (BSE)
3. Wasting disease of deer & elk
 Humans:
1. Kuru (no longer around)
2. Creutzfeldt-Jakob disease (most common TSE in USA)
a. Incidence: 1 per million per year
b. Incubation: up to 50 years
c. Mortality: 100%
3. Variant CJD (what people mean when they say a human has “mad cow disease”)

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

Kuru: Fore people group in Papua New Guinea; very isolated.

 Big epidemic of Kuru (= “trembling”) especially among women and children (7 of 8)
o Cerebellar dysfunction, then rapid decline
 Autopsy: no inflammation, no characteristic cellular changes, just loss of Purkinje cells
 Similarities to scrapie identified; inoculated primates with Kuru pt. brain, 2-4 yrs later had kuru (1st transmission
of human infection to subhuman primates, nobel prize, etc.)
 Ritual cannibalism was the cause: started in 1900s, suppressed in 1960s by Australians
o Men would eat more choice cuts
o Women & children would eat brains & other parts
o 50+ year incubation: cases from 50s  today (last few)

 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
 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)

 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

Mad cow disease (BSE)

 Started 1985, England
 Looks like scrapie in cow; didn’t do anything about it, big explosion of cases
 Pattern: throughout England, Scotland, Wales; one case pretty much everywhere (opposite of kuru/scrapie)
o Point-source epidemic
 Bone meal: from all kinds of sources. Cook “greaves” (random animal parts), extract tallow (candles/fat/etc),
get bone meal (for cattle feed; helps calves grow faster)
o 1980s: Iranian gas crisis: short-cuts on cooking of various bone meal prep steps
o 1979: tallow market crash: people decided animal fats were bad for you, switched to vegetable fats
 Stopped processing tallow & left fat (with infectivity) in
 1988: banned cattle carcasses in cattle feed; 1989: banned cattle offal in human food
o After 5-year lag (incubation period), cases started to drop

 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

US food chain concerns:

 imported BSE cattle
 spontaneous BSE in cattle/other animals
 chronic wasting disease in deer and elk (clearly spreading among captive and live deer)

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

 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

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

New viral agent: HIV.

 14,000 new infections/day, 42M living with HIV, 4.3M newly infected 2006, 2.9M deaths/year, 2.2M on ART
 Huge reduction in life expectancy in some African countries (negated all health gains since 1950s)
 PEPFAR continuing to give aid to developing countries; widely expanded in ’08 & focused on across-the-board
health care systemic improvements (and monitoring outcomes, not just # treated or prevented anymore)


 1996 AIDS conference, Vancouver: viral dynamics / # copies Cancer chemo 10 months
explored; clinical trials of triple therapy reported Coronary bypass 20 months
 Protease inhibitors: great example of rational drug design HAART-HIV 43 years
 Now 26 drugs across 6 classes; huge improvements in outcome & survival
 New focuses: Cure HIV (2009 case; empty latent pool); eradicate HIV (test & treat)
 (FYI: HCV antiviral agents represent 28% new drug apps for antimicrobials)

New antibacterial agent: the bacteria

 Great achievement; abused  microbes win!
 MRSA: USA-300, community-acquired; USA-100: hospital-acquired; necrotizing fasciitis & pneumonia
 Pipeline of Abx drying up (fewer approved & just one new class in 20 years): pharma wants to make drugs you
have to take every day!

Infectious disease epidemic: Influenza

 H1N1 (1918): 25-30% world’s population ill; >40 million deaths worldwide (60% in 20-45yo)
o Influenza usually kills old (85+) but avg age in 1918: 28 years old (same with avian influenza today)
 Bird flu today: controlled in birds (vaccines / culling), by isolating patients, and because virus hasn’t gotten good
at human-human transmission yet
H1N1 challenges
 H1N1 today: people born before 1957 not getting this one – H1N1
circulating until 1957.  Vaccine production (solved – 15 μg,
no adjuvant, single dose – but late)
 Seasonal = 65+yo, swine flu = young people
 Antivirals (OK for now)
 Currently at pandemic alert level: 4 influenza pandemic, totally

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

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)
 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;
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

Infection site: ANO2: FREQUENT ANO2: RARE

 Why not UTIs? Urine isn’t Brain abscess, dental
Meningitis, pharyngitis,
appropriate for replication of HEAD & NECK infections, space infections,
acute sinusitis, acute otitis
anaerobes (reduction potential) chronic sinusitis, chronic otitis
 Almost all abdominal abscesses Aspiration pneumonia, lung Bronchitis
(except those in table) usually abscess, empyema Non-aspiration pneumonia
have anaerobic involvement Cholecystitis, spontaneous
ABDOMEN Peritonitis, phlegmon/abscess
 Dental infections: 1000:1 bacterial peritonitis
anaerobes:others in gingival GU TRACT Female genital tract UTIs, STDs
crease; during extraction or other damage, anaerobes can pass to perimandibular space (through mandible &
underneath) and set up infection there.
 “Clenched fist injury” – punch somebody in the mouth & their anaerobes get you back with a nasty infection
 When you see abscess or aspiration pneumonia, think ANAEROBE

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

Anaerobes & Anaerobic Infections: Summary

 Important, neglected, predominant flora, 1 quadrillion per person
 Endogenous infections, abscessogenic or clostridial toxins
 Dx: clinical clues; Rx: empiric

Chlamydia & Mycoplasma
 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)

Biphasic life cycle:

1. Elementary body (like spore) attaches to, ingested by cell
2. Phagosome fusion; EB  reticulate body (RB)
3. RB multiplies, condenses (RB  EB), forms inclusion body
4. Inclusion body releases EB (infectious particle)
(EB: infectious, not metabolically active; RB: metabolically active, not infectious)

 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

Multiple serotypes with different diseases (note conjunctivitis ≠ trachoma)

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
 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

 Same life cycle as C. trachomatis; spread via respiratory route

 Common cause of upper & lower resp. infections
o 7-10% of CAP
o “Atypical pneumonia” – interstitial, not lobar like S. pneumoniae, etc.

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

Tiny prokaryotes, lack a cell wall; Cell membrane bound: contain sterols; has RNA, DNA; hard to grow (special agar)

Mycoplasma pneumoniae: URTI & atypical pneumonia (respiratory aerosols)

 Can have complications (derm, cardiac arrhythmias/CHF, neuro: meningitis, encephalitis)
Mycoplasma genitalium: urethritis & cervicitis
 No cell wall; unknown prevalence, not reportable; sequelae unknown
o Smallest prokaryote bacteria capable of self-replication; culture often missed, PCR?
Treatment: Doxycycline, macrolides, fluoroquinolones

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
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

 NTM: large; diverse group

o M. tuberculosis complex
 M. TB; others including M. bovis (attenuated to vaccine strain, M. bovis BCG)
 Mycobacterial cell wall: like a Gram (+) at heart but covered with an outer lipid layer
o Mycolic acid & certain glycolipids are unique to mycobacteriae & nocardia
Diagnosing Mycobacteria
AFB Test
 Rapid diagnostic test (real time!); specific for mycobacteria, but don’t know which species!
 Sensitivity only 40-70%: need high amount of AFB to visualize. CAN’T EXCLUDE TB WITH NEGATIVE SMEAR
 Fluorescent acid-fast stains make visualization quicker & easier to read (e.g. auramine-rhodamine fluorescence)

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

Rapid Dx: Nucleic acid amplification (like PCR)

 More sensitive than smear; less sensitive than culture (90% sputum+ samples; 50% sputum- )
 Positive test: supports TB Dx; NEGATIVE TEST DOES NOT EXCLUDE TB
 Good for specimens other than sputum

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

 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)
↑ 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

Immunologic reactions: (can occur after Tx: unleash immune response)

 Reversal reaction
o Treatment of BB (borderline) disease can cause Leprosy Dx
immune reconstitution  DTH reaction Examination:
o Inflammation of existing lesions  erythematous / hypopigmented skin lesions
o Requires corticosteroid Tx (prevent further  + sensory loss
motor/sensory loss)  ± enlarged peripheral nerves
 Erythema nodosum leprosum
o BL/LL disease: can develop fever, eruption of red Lab: skin smear / biopsy; PCR-based if available
nodules, other inflammatory manifestations
o Already have high burden of organism; may be due to immune complexes
o Can require corticosteroids
Non-tuberculosis Mycobacteria (NTM)

 Free-living, environmental, opportunistic pathogens Main clinical scenarios of NTMs

o Need to distinguish contamination from actual infection 1. Lymphadenitis
2. Inhalational pulmonary disease
Slow-growers: M. avium complex; M. kansasii, M. marinum, M. ulcerans 3. Disseminated disease
Rapid-growers: M. abscessus, M. chelonae, M. fortuitum 4. Skin/skin structure infection
(following inoculation)

Mycobacterium Avium Complex (MAC/MAI)

= Mycobacterium avium-intracellularae: really two organisms
 Environmental organism (soil/water)

Main clinical syndromes

 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
 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
 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

Cutaneous Nocardosis: immunocompentent host

 Manifestations: Celulitis / abscess / lymphocutaneous (can track up lymph vessels)
1. Mycetoma (N. brasiliensis only)
 Common where shoes aren’t worn
 Host & microbe interact, chronic inflammation
 Huge exophytic (growing outward) ulcerative masses; ooze & pus)

Pulmonary & Disseminated Nocardosis

 Host: reduced cell-mediated immunity
 Nodular/cavitary infiltrates; disseminates to brain / skin
 Diagnosis: difficult: no pathognomonic features; often not suspected; may delay Dx procedure (pt
immunocomporomised); may be partially treated / difficult to isolate after empiric Tx
1. Pulmonary AND brain disease
2. Nodular / cavitary
3. Immunosuppresed

Order: Actinomycetales

Cavitary lung disease;

risk for dissemination if immunocompromised
Risk: impaired cell-mediated immunity
Acid-fast (mycolates in cell wall)

Can be cultured on blood agar

Filamentous rods

Ubiquitous in environment
Latent infection; gives +
tuberculin skin test
Slower generation time
Longer mycolates
(more resistant to
decolorization; more acid-fast)

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

 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
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

Principles of antibiotic treatment

1. Develop differential diagnosis
o Most likely disease states based on history and Principles of Antibiotic Treatment (overview)
physical exam 1. Develop differential diagnosis
 Demographics: age, race, geography, 2. Determine if antibiotics are necessary
speed of onset, rapidity of progression, 3. Choose an antibiotic
course 4. Refine antibiotic choice
 Organ systems affected, 5. Have a plan for length of therapy
signs/symptoms, prior Dx & therapies
o Is there an infectious process on the short list?

2. Determine if antibiotics are necessary right now

o Does antibiotic therapy alter the course of disease?
 No effect on some mild bacterial infections: especially those with primary viral problem (acute
bronchitis, acute sinusitis, acute otitis media) or natural mechanism to clear (infectious
o Are antibiotics required immediately?
 Risk/benefit: risk of deferring therapy vs benefit of waiting to confirm dx
 known focus of infection that requires tx with  Stable patient with subacute process in
abx to prevent the patient from getting sicker whom culture data may be hard to obtain but
(acute meningitis, pneumonia, acute is critical to management
endocarditis, epidural abscess with cord
compromise, etc.) (pt with fever of unknown origin: get origin
first, suspected vertebral osteomyelitis w/o
 no known focus of infection but other neurological sx, pt with wt loss & mass-like
important feature lesion in right middle lobe of lung:
(neutropenia/cancer + fever, asplenia + fever, malignancy?)
high immunosuppression + fever, toxic-
appearing patients with unstable vital signs)

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.

4. Refine antibiotic choice

o Keep an open mind. Follow progress over time; reassess DDx if not progressing as expected
o Watch for & anticipate side effects:
 Allergies: PCNs, other drugs
 Drug-drug interactions (know current meds)
 Rifampin (oral contraceptives), voriconazole/posaconazole, erythromycin
 Look out for pts on warfarin, oral contraceptives
 Drug-food interactions: antacids inactivate oral fluoroquinolones

5. Have a plan for length of therapy

When to stop antibiotics?
o Empiric treatment:
 trust cultures & stop if from sputum/blood/urine before antibiotics started aren’t growing
organisms (not pneumonia, bacteremia, UTI)
 MRSA and pseudomonas grow easily: if they’re not isolated in culture, they’re most likely not
there and you don’t have to cover them
 NO REQUIREMENT TO “COMPLETE A COURSE” just because you started empirically
o Pathogen-directed treatment
 Length of most courses of therapy: arbitrary multiples of 7 days!
 Some have been clinically investigated: S. aureus bacteremia w/o endocarditis (14-28d); N.
meningitidis meningitis (7d), uncomplicated UTI in woman (3d)
 Try to give shortest course possible

Cultures & Antibiotics

Common error: antibiotics for every possible culture. Make sure to evaluate the culture!
Blood cultures
S. aureus (coag +)
Usually don’t treat
Coag (-) Staph Usually a contaminant Exceptions:
Gram (+) rods (skin organisms)  patients with indwelling hardware
 signs of infection & >1 positive culture
Evaluate clinical picture for possible source (e.g.
Strep viridans
50/50 oral, GI, endocarditis)
 signs of infection & >1 positive culture

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

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. 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.

Explaining antibiotic control to patients:

 educate physicians + patients + office staff (not effective to focus on one group, have office-based materials,
reinforce education during well-patient visits)
 Patients: explain, share facts (not for viral infections), build cooperation & trust, don’t say “just a viral infection”,
get pt involved, give alternative Tx for symptoms when possible, be confident

Pharmaceutical representatives: varying perception about appropriateness of gifts; people think that it only affects
other doctors & not me, etc.

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
 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
(Klebsiella granulomatiosis)
 Urethral/vaginal/cervical inflammation; proctitis (receptive anal sex), pediculosis pubis too.

Syphilis (Treponema pallidum)

“The great imitator / imposter” – can cause disease in pretty much any internal organ

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

Transmission: primarily sexual contact; also kissing, in utero, blood transfusions

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)

Stages (natural history: assume no treatment)

1. Primary syphilis Early neurosyphilis
a. Chancre: single papule at site of inoculation  ulcer;  CNS involvement can be
painless, well demarcated, heaped-up edges, smooth base, symptomatic during primary or
highly vascularized. secondary syphilis
i. Heals in 3-6wks without therapy  Presentation like meningitis (stiff
ii. If grouped, painful ulcer neck, headache, photophobia)
iii. Harder to recognize in women (more likely to have  Usually self-resolving ( immune
worse outcomes with syphilis) system can control)
 More common in HIV patients
2. Secondary syphilis
a. Lymph nodes  blood, multiplication & dissemination
b. 2-8 wks after chancre if untreated: most common = skin manifestations (rash on palms & soles is classic
for secondary syphilis, but can look like anything! Macular/popular/ulcers/pustules/psoriasis/etc)
c. Skin lesions: filled with tons of spirochetes, very infectious (only if both people have abrasions on skin)
i. Condyloma lata: gray raised lesions; look papillomatous, almost like genital/anal warts
ii. Mucous patches in mouth, etc.
d. Other manifestations: all organ systems possible or even asymptomatic (even without rash)
i. Fever, lymphadenopathy, meningitis, optic neuritis, gastritis, hepatitis, glomerulonephritis, arthritis

3. Latent syphilis: no manifestations at all!

a. Immune system controls secondary manifestation; patient becomes Asx (latency)
b. Early latency: 1st year, pt. can have relapses of secondary syphilis; still infectious
c. Late latency: > 1 yr, pt is immune to relapse or reinfection
ii. 60% will stay in late-latent forever! (even without treatment)
iii. 30% will develop late syphilis & its manifestations if untreated

4. Late syphilis: a.k.a. “tertiary syphilis”; occurs decades later

a. Cardiovascular syphilis
i. Endarteritis obliterans of vasa vasorum of the aorta  aortitis  sacular aneuyrisms
1. FYI: Endarteritis obliterans = “inflammatory condition of the lining of the arterial walls in which the intima
proliferates, narrowing the lumen of the vessels and occluding the smaller vessels”
2. Usually ascending aorta; used to be most common cause of aortic aneuyrisms
b. Gummatous syphilis: almost like TB
i. Benign, granulomatous-like lesions usually affecting skin / bones but can occur in any organ;
causes local destruction via immune response
ii. Called “Gummas”, especially common in face & nasal cartilage (path: look like TB granulomata)
iii. “Benign” unless they’re in a bad place (heart, etc).
c. Late neurosyphilis: can be symptomatic or asymptomatic
i. Symptomatic: >10yr after primary infection; 2 main groups (meningovascular/parenchymatous)

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
 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)

 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)

 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

1. Non-treponemal tests: RPR & VRDL

 RPR = rapid plasmid reagent; VRDL = venereal disease research laboratory
 Nonspecific but very sensitive (almost 100%); quantitative
 testing for anticardiolpin IgM & IgG (marker of host cell – treponeme interaction: looking for Ab
against mitochondrial self-antigens; treponemes make cells explode & immune response against
these Ag follows)
 VERY CHEAP: 1st test to get if you suspect syphilis
 Result negative & don’t suspect primary syphilis: unlikely to have syphilis, no more tests
 Result positive: confirm by ordering treponemal test
 Provide titer that can be followed (1:1 = low, 1:2048 = very high; want 4-fold reduction in 12
months to indicate a cure)
 Re-test to follow treatment & check for re-infection

2. Treponemal tests: test for treponemal-specific antibodies;

 Tests are specific but expensive (use RPR/VRDL first)
 Don’t provide a titer that can be followed after therapy; once-positive = always positive

Treatment: need both a good immune system and penicillin to cure

 PENICILLIN; dose depends on stage of disease
o Early: 2.4M units PCN x1 dose
o Late-latent (gummas, etc.): 2.4M units PCN x3 doses over 3 weeks
o If patient is PCN-allergic: desensitize & use PCN anyway
 Treat patient and ALL SEX PARTNERS (track down & treat, even if you have to use the police to do it)

Other diseases (DDx)

STI DDx: Genital ulcers
 Granuloma inguinale donovanosis:
o From Klebsiella granulomatis, rare in US (more SE Asia, Africa)
o Painless, progressive, ulcerative lesions without regional lymphadenopathy
o “beefy red” & highly vascular
Painless ulcers Painful ulcers
o Dx: tissue biopsy (no culture; PCR not FDA approved)
Syphilis, LGV, Herpes,
o Rx: doxycycline (100 mg po BID x 3wks)
granuloma inguinale chancroid
 Chancroid
o From Haemophilus ducreyi, endemic in some parts of southern US
o Painful genital ulcer & tender supperative inguinal adenopathy; often co-infected (syphilis / HSV)
o Dx: culture
o Rx: azithromycin 1g po x1 or ceftriaxone 250mg IM x1

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

STI DDx: Pelvic inflammatory disease

 Infection spreading to upper genital tract in women (uterus/fallopian tubes/ovaries) (STIs in general)
 Symptoms: abdominal pain, fever
 Signs: uterine tenderness and cervical motion tenderness
 Complications: infertility, chronic pelvic pain, ectopic pregnancy

STI DDx: Proctitis

 N. gonorrhoeae, Chlamydia trachomatis, HSV 1&2
 Can be infected but asymptomatic
 Generally via receptive anal sex
 Symptoms: pain on defecation, rectal discharge with blood & mucus

General principles of STI management:

 NO SEX (even with a condom) until patient and partners are treated
 Find one STI  test for ALL THE OTHERS
 Most STIs are reportable infections: report to health department
 When possible, use a treatment that you can watch them take(e.g. PCN injection)
 Don’t judge patient (better to get partners treated, etc)