- Economic and productivity influences

- Higher impact for children under <5 years old

- Children are more susceptible to diarrhea, malaria, and measles

- ~ 6 million children die worldwide each year

- Most disease are preventable

- Chronic infectious diseases --> Affect quality of life/disability and create a huge burden on the health care system

- 1 in 6 cancer cause be preventable and treatable infectious diseases --> HPV, Hep B, Hep C, and H. pylori

- Only have successfully eradicated small pox

- Polio is almost entirely eradicated but still around

- Eradication hindered by political, religious, economic, and trust issues around the world

- Problems in developed countries with the disputed connection between Autism and vaccines

- Requires four things

1. Effective epidemiological surveillance

2. Environmental sanitation and infection control

3. Implementation of immunization programs

4. Correct diagnosis and treatment of infections

- Emerging and re-emerging infectious diseases --> 2/3 of diseases now are zoones

- Increased number of elderly and immunocompromised people

- Hospitals and invasive procedures & devices

- More food orignates outside the home

- Use of antimicrobial drugs

- Evolution of resistant, more virulent, and "vaccine-resistant" strains

- Make up the normal flora --> Microbiome

- Present in everyone all the time

- One benefits while the other neither benefits nor hurts

- Sources for opportunistic infections

- Usually present in the normal flora

- Become pathogens when host becomes immunocompromised or when the pathogen moves from his normal location

- Only associated with disease in the host

- Ex. Rabies, mycobacterium tuberculosis

- Usually not pathogenic

- Organisms that are present in some but not in others

- Colonize area for a time and then go away

- Usually transient

- Ex. N. meningiditis --> Asymptomatic in the URT

- Other people by direct transmission

- Vertical transmission (mother to fetus)

- Fomites: On inanimate objects

- Indirect transmission: Animals, insects, contaminated food, and water --> Many infections are caused by animal contact

- Healthcare-associated Infections: From procedural devices and machines

- Normal flora/microbiome

- Germ Theory

1. Must be found in the body in all cases of diease

2. Must be isolated from the case and cultured

3. Must reproduce the disease from culture in another host

4. Must culture again from the other host

- Flu-like symptoms

- Fever

- Chills

- Myalgias

- Loss of appetite

- Leukocytosis --> High WBC count and neutrophil count

- Due to innate immune response and TNF and IL-1

- Bands > Segs/polys

- Organism specific

- Usually confined to specific area of infection

- Erythema

- Inflammation

- Diarrhea

- Stomach pain

1. Availability of new drugs is shrinking due to resistance

2. Be familiar with new technology for identifying bugs

3. Beware of nuances treating S. aureus

4. Always remember C. difficile!!

5. Take out unncessary IVs

6. Be aware of urinary catheters and UTI risk

7. Urine culture without simultaneous urine analysis is worthless

8. Bactrim does NOT treat Strep

9. Take proper precautions with norovirus

10. Never swab decubitus ulcer unless clearly infected!!

- E. Coli UTIs

- HIV

- Staph bacteremia

- Pneumonia

- Meningitis

- Cellulitis

- Diabetic foot infections

- Osteomyelitis

- Spontaneous peritonitis

- Infections in immunocompromised hosts --> Opportunistic

- Tuberculosis

- Microorganisms frequently found on or in the body of health persons --> Outnumber human cells 10-fold

- Cannot live without them!!

- Mostly anaerobic bacteria but also fungi, bacteriophage, and parasites

- Some are culturable while others are non-culturable

- Human Microbiome Project --> Determine health microbiome to see if it's different from those present in diseased patients

- No two microbiomes are alike --> Diversity is huge, even in just one person

- Still a few signature bacteria found in body sites

- Fetus grows in a sterile environment

- Becomes colonized during either vaginal or C-section deliveries

- Different subset of bacteria found depending on type of birth

- Also colonization depends on whether the mother breast feeds or not

- Gut bacteria colonization allows for increased carbohydrate break down of mother's milk

- Further colonized but interaction with family and environment

- Quite dynamic

- Change with age, change in diet, location, work environment, immune status, hormone levels and medications

- Clumps of bacteria within microbiome that become attached to the epithelial surface

- Usually attach the surface via pioneer bacteria

- Sometimes are present in biofilms

- Microcolonies then develop

- Other bacteria attach

- Palisading of bacteria --> Structure of a more "mature" microbiota/plaque

- Large intestine --> Highest density!!

- Skin

- Upper respiratory tract

- Mouth

- Vagina

- Anterior part of the urethra

- Pathogen displacement --> Takes up space

- Nutrient competition

- Receptor competition

- Production of anti-microbial factors

- Fortifies epithelial barriers

- Induces IgA production

- Induces apical tightening of tight junctions

- Helps develop immune system

- Controls intestinal epithelial cell differentiation and proliferation

- Metabolizes dietary carbohydrates

- Synthesizes vitamins --> Vitamin K, biotin, and folate

- Ferments non-digestible dietary residues and endogenous epithelial-derived mucus

- Aids in ion absorption

- Helps to salvage energy

- Gut bacteria can activate or inactivate drug

- Produce a toxic byproduct

- Produce an antimicrobial product

- Hygiene hypothesis

- Use of antibiotics clears out the normal gut flora

- Immune system ends up being under developed

- Alters antibody production to have IgE antibodies predominate

- IgE production induces eosinophil expansion

- Predisposes these people to allergic disease and asthma

- Normal flora actually stimulates immune system and helps develop it

- Keeps flora in check with IgA antibodies, mucous membranes, and microbials

- Underlying APCs and dendritic cells are constantly sampling the environment and responding to the bacteria encountered

- M-cells engulf pathogens and release them to the underlying APCs to initiate immune response

- Commensals fail to inhibit the NF-kB signaling pathway

- Pathogens do stimulate NF-kB signaling pathway

- Most important: Staph. aureus, coag-neg Staph., and Corynebacterium species

- Less important: Haemophilus spp and Streptococcus spp.

- Most Important Organisms: Staph. epidermidis

- Other: S. aureus, Corynebacterium, various Strep., Pseudomonas auruginosa, anaerobes, and yeast

- Most Important: S. aureus

- Other: S. epidermidis, Corynebacterium, and various Strep.

- Most important: Viridans streptococci

- Other: Streptococci and Elkenella corrodens

- Most Important: Streptococcus mutans

- Other: Prevotella intermedia and Porphyromonas gingivalis

- Most imporant: Various anaerobes (Bacteroiodes, Fusobacterium, Streptococci, and Actinomyces)

- Most important: Viridans streptococci

- Other: Various streptococci, Neisseria spp., Haemophilus influenzae, S. epidermidis, and Moraxella

- Normally almost none

- Other: Helicobacter pylori, Lactobacillus spp. and Streptococcus spp.

- Most important: Bacteroiodes fragilis and E. coli

- Other: Bifidobacterium, Eubacterium, Fusobacterium, Lactoacillus, various Gram-negative rods, Enterocccus faecalis, Streptococci spp., and Clostridium spp.

- Most important: Lactobacillus spp., E. coli, and group B Streptococci

- Other: Various Streptococci, various Gram-negative rods, B. fragilis, Corynebacterium spp., and Candida spp.

- None are extremely important

- Others: S. epidermidis, coag-neg Staphylococcus spp., Corynebacterium, various Streptococci, various Gram-negative rods (E. coli)

- Deep tissues and organs

- CSF

- Blood

- Body fluids --> Urine

- Dysbiosis

- Obesity and metabolic syndromes

- Inflammatory bowel disease

- Irritable bowel syndrome

- Asthma

- Antibiotic-associated diseases

- Autoimmune and inflammatory diseases

- Colon cancer

- Non-alcoholic fatty liver disease

- Atopy

- Hypertension

- Live microorganisms that confer a health benefit on the host

- Must be administered in adequate amounts

- Selectively fermented ingredients that stimulate specific changes in colinic microbiota

- Benefits the health of the host by stimulating microbiota growth

- Combination of pre and probiotics

- Designed to have a synergistic effect on benefit for the host

- Used in cases of severe microbiota dysbiosis

- Recurrent C. difficile infections even after cessation of antibiotics

- Process of determining the pathogen responsible for disease

1. All lab tests have potential for inaccuracy

2. Lab tests vary in sensitivity and what they measure

3. Identification of organism doesn't mean it is causing disease

4. Lab tests are just part of the picture!!

- Direct testing

1. Staining --> Gram or specific

2. Streak plate isolation --> Hope to get down to single colonies to observe appearance

3. Identification using tests and antibiotic susceptibility tests

- Some tests take longer than others

- Some look for toxins instead of bacteria

- Observe colonies: Apperances, hemolysis and odor

- Hospital specific antibiotic susceptibility tables are available!!

- Indirect detection

- Serology

- Detects antibody levels

- Acute serum: At or near onset of symptoms

- Convalescent serum: Taken at least 14 days after

- 4-fold increase in IgM antibodies --> Acute infection

- IgG antibodies --> Previous infection

- Sampling or transport conditions are not favorable for organism

- Organism is non-culturable

- Molecular assay are unavailable

- In infections with bacterial shedding occurs before symptoms appear --> Bacteria would no longer be present in any samples taken

- Used with systemic infections/sepsis, endocarditis, meningitis, pneumonia, etc

- Gram-positive and Gram-negative bacteria can be responsible

- Need multiple specimens over 24 hours (2-3 tubes)

- Risk for contamination from skin (S. epidermidis) 

- Special culture tubes are now available --> Don't need to open

- Be sure to collect before starting antibiotics!!

- Taken for pharyngitis/sore throat

- Want to swab the tonsils and the uvula

- Also swab pus containing sores if present

- Most commonly caused by viruses

- Bacterial causes: Strep. pyogenes (Group A)

- Cultured on blood agar usually

- Examine hemolysis

- Ordered when TB, lobar pneumonias, and atypical pneumonias are suspect

- Specimen from the lower respiratory tract

- Collected  through coughing

- Must try not to contaminate with oralf flora

- Lab won't accept if too many squamous cells are present --> Contamination

- WBCs and mucous strings present on slide

- CSF is normally sterile

- Taken when meningitis is suspected

- Needle inserted between L3 + L4

- Cultures could come back negative --> Bacterial, fungal, and viral causes

- Common causes: N. meningiditis, S. pneumoniae, H. pneumoniae (elderly), and Cryptococcus neoformans (immunocompromised)

- Stained for WBCs to determine number

- Number differentiates between invasive and toxigenic organisms

- Variety of agars for culturing

- Urine should be sterile

- Easily contaminated by vaginal and skin flora simply due to normal flow

- Count CFUs present --> >100,000 CFUs/mL means UTI

- Try to obtain a mid-stream catch to decrease contamination

- Taken when STDs are suspected

- Pap smears for women or culturing a pus filled wound

- Organisms are very fastidious/fragile so must be handled with care

- Never culture decubitous wound unless clearly infected!!

- Clostridium in wounds covered with dirt

- S. aureus commonly in abcesses

- Animal and human bites show different bacterial infections

- Gram-positive cocci in clusters --> 40 different species

- Species: G. aureus, S. epidermidis, and other coag-neg. Staphylococcus

- Transient colonizers or part of normal flora

- Facultative anaerobes

- S. aureus: Yellow and B-hemolytic

- S. epidermidis: White, non-hemolytic

- Acquired by phage or another mobile genetic element

- Teichoic acid and lipoteichoic acid

- Some are encapsulated

- Protein A (S. aureus): Binds IgG antibodies

- Adhesion molecules --> Pili

- Production of toxins and enzymes

- Look similar on gram staining --> G+ cocci

- Cause many of the same diseases --> impetigo, toxic shock syndrome, and endocarditis 

- Catalase test

- Strep is neg. --> In chains

- Staph is pos. --> In clusters

- Both are facultative anaerobes though

1. Coagulase test

- S. aureus --> Coag +

- S. epidermidis --> Coag -

- Lots of resistance in S. aureus but NOT in S. epidermidis

2. Growth on mannitol/salt agar

- Coag-neg. Staph: Growth but no color change

- S. aureus: Growth with color change 

- Commonly found in the nostrils

- Skin-to-skin contact, fomites, and endogenous sources

- Liquid soaps can also be contaminated

- Commonly transmitted in hospitals, prisons, immunocompromised people, football players, and wrestling

- Respiratory and animal transmission also possible

1.Skin infections most common: Abcess/boil containing leukocytes, necrotic tissue, and live/dead bacterial cells --> Surrounded by erythema and inflammation

2. Virulence factors: Protein A, capsule, adhesion molecules, toxins and enzymes

3. Toxins

4. Enzymes: Coagulase, hyaluronidase, staphylokinase, clumping factor, and lipase

5. Hemolysins and leukocidins produced

6. Diseases: Osteomyelitis, endocarditis, and pneumonia

- Folliculitis: Infection of the hair follicle

- Furuncles: Infection in fused hair follicles

- Carbuncles: Infection is large and extends deeper

- Stye: Infection of the eyelash

- Impetigo: Superficial infection usually on the face and limbs on children

- Bullous impetigo: Has blisters that never rupture

- Cellulitis: Deeper skin infection with no clear demarcation

- Abcess/empyema: Characteristic of S. aureus infection, need to be drained

- Can be caused by Staph or Strep

- Mediated by toxic shock protein --> Superantigen

- Toxin mediated

- Symptoms: Sunburn rash, desquamation, fever, hypotension

- Superficial skin disease caused primarily by S. aureus

- Caused by exfolliative toxin --> Superantigen

- Commonly caused by S. aureus

- Enterotoxin A-R

- Causes nausea, vomitting, and diarrhea

- Bacteria may already have shed by the time cultures are taken

- Must test for toxin instead

- Hot compresses

- Drain abcess

- Remove prothetics if necessary

- Antibiotics but must treat with the right one for particular strain

- Superbug --> USA300 strain is the most virulent, contagious, and survives the longest

- Not just hospital acquired anymore

- Antibiotic resistance: Plasmid transfer of pathogenicity island

- Good hygiene

- Prophylactic antibiotics only in special conditions

- No vaccine available

- Normal flora on skin

- White, non-hemolytic and coag. negative

- Novobicin-sensitive

- Treatment: Vancomycin

- Diseases: Osteomyelitis possible

- White, non-hemolytic, and coag-neg.

- Novobicin-resistant

- Common cause of UTI

- Usually transmitted through sexual contact

- Gram positive cocci in chains (usually short)

- Catalase neg. 

- Groups A-R based on antigenic variation

- S. pyogenes (Group A), S. agalactiae (Group B), Enterococcus (Group D), S. pneumoniae, and Viridans streptococci

- Varying levels of hemolysis

- Group A strep: B-hemolytic

- Normal flora in throat

1. Virulence Factors: Capsule, pyrogenic exotoxins, and M protein

- Capsule: Made of hyaluronic acid

- M protein: Fimbrial antigen (>80 types) --> Mediates disease

2. Enzymes: Hyaluronidase, streptolysin A+O, streptokinase, NADase, streptodornases, and C5a peptidase

3. Toxins --> Pyrogenic/erythrogenic exotoxins and toxic shock syndrome

- Pyrogenic exotoxins --> Necrotizing fasciitis

4. Diseases: Meningitis, otitis, sinusitis, tonisilitis, pharyngitis, adenitis, pneumonia, endocarditis, skin, Scarlet Fever, and necrotizing fasciitis

- Usually caused by viruses

- Bacterial cause: S. pyogenes

- Can spread to otitis, meningitis, or Scarlet Fever

- Due to S. pyogenes in the throat

- Results when exotoxins are produced by bacteria

- Presents with high fever

- Rash starting on upper chest, spreading to the extremities but sparing the palms and soles of the feet

- Strawberry tongue possible

- Well demarcated

- Usually only on the face

- Caused by group A strep

- Impetigo also possible due to group A strep

- Caused by group A strep

- Highly destructive skin disease

- Site needs to be debreeded and possibly amputated

- Pathogenesis mediated by exotoxins and the resulting immune response

- Sequelae following skin infections

- Due to immune complexes building up in the kidney

- Type III hypersensitivity

- Immune complexes produced to the M protein of S. pyogenes

- Symptoms: Red face, hypertension, and smokey urine

- Caused by group A strep pharyngitis

- Autoimmune cardiac dysfunction occurs upon re-infection with group A strep

- Type II hypersensitivity

- Symptoms: Arthralgia, polyarthritis, and carditis

- Bacitracin resistance test

- Group B is resistant

- Group A is sensitive

- Also rapid tests available for group A strep

- Treatment: Penicillin and prophylaxis for patients with or at risk for Rheumatic Fever

- Prevention: Good hygiene but NO vaccine

- Group B Strep

- B-hemolytic

- Passed from mother to baby --> Neonatal meningitis and possibly sepsis

- Virulence: Not well understood

- Bacitracin resistant

- CAMP test for Group B: + test enhances S. aureus hemolysis

- Treatment: Penicillin and prophylaxis in pregnant women

- G+ diplococci surrounded by capsule --> A-hemolytic

- Most common cause of community-acquired lobar pneumonia --> Present in all age groups except newborns

- Assymptomatic carriers possible

- Transmission: Respiratory droplets

- Virulence Factors: Capsule, IgA protease, pneumolysis, teichoic acid, peptidoglycan, and phosphocholine

- Diseases: Otitis, sinusitis, meningitis, and sepsis

- Optochin-sensitivite --> Testing method

- Treatment: Penicillin and 2nd generation cephalosporin

- Vaccines: PPSV23 and PCV-13

- Usually doesn't cause disease in healthy people

- Can cause endocarditis and dental caries

- Ex. Strep. mutans --> Dental cavities

- G+ cocci --> A-hemolytic

- Optochin resistant

- Group D strep

- G+ cocci in chains

- Grow in presence of high salt and bile

- Enterocuccus faecalis --> Common catheter acquired UTI

- 

- Many present as normal flora of the throat

- Gram-neg. diplococci --> "kissing coffee beans"

- Fastidious growth requirements and fragile

- Transmission: Close contact, usually through sexual contact

- Only grows on Thayer-Martin agar --> Heated blood agar and antimicrobials to help Neisseria spp.

- Virulence Factors: Pili, LOS, porin proteins, Opa proteins, and some have capsules

- N. meningiditis --> Can ferment glucose and maltose

- N. gonorrhoeae --> Can only ferment glucose

- Grows intracellularly in neutrophils

- Men are almost always symptomatic with purulent discharge

- 50-80% of women are assymptomatic --> Need PCR to diagnose

- Classified into strains based on pilin proteins

- 2nd most common bacterial STD --> Highest rates in 15-24 year olds

- Strict human pathogen

- Transmission: More likely transmitted from man to woman (~50%)

- Aided by immune response

- Endocytosed by mucosal cells

- Transported to subendothelial space by mucosal cells

- Inflammation induced in subendothelial space by LOS and porins binding PRRs on APCs

- Late complement is crucial in immune response

- Virulence Factors: IgA protease, B-lactamase, pili, Opa protein, porins and LOS

- Antibodies are developed to virulence factors but antigenic variation is very common

- High re-infection rate

- Infection sites: Genital tract, rectum, conjunctiva, and oropharynx

- Incubation period: 2-14 days

- Symptoms: Present after 2-5 days

- Symptoms usually mild in women --> Painful urination and increased vaginal discharge

- Symptoms in men --> Purulent discharge, inflammation of urethra and painful urination

- Due to assymptomatic presentation --> Can lead to infertility and disseminated disease (sepsis)

- Men: Gram staining of purulent exudate from urethral specimens

- Women: PCR necessary

- Treatment: 3rd generation cephalosporin and azithromycin

- Penicillins and tetracylcines are NOT recommended

- Prevention: Safe sexual behaviors --> No vaccine

- Neisseria meningitidis

- Endemic disease in Africa --> Primarily in children

- ~ 1,000 cases/year in the US

- Common in dry, cold months

- Transmission: Respiratory droplets and close contact

- Humans are natural carriers in the nose --> 20-30%

- Highly invasive --> Can go through cells and into blood

- Endotoxins can induce sepsis

- Encapsulated --> Increases virulence

- Symptoms: Fever, headache, stiff neck, light sensitivity and rash

- Purpura/meningiococcemia rash --> Can result due to blood infection

- Antibodies produced --> Protective against re-infection

- Complement-mediated killing is crucial

- Inflammation: Sepsis can result from TNF-A and other inflammatory mediators

- Treatment: Penicillin and 3rd generation cephalosporin

- Prophylaxis given to people in contact with a case --> Antibiotics and vaccine

- Vaccination: Based off of capsule --> Polyvalent vaccines

- Pharmacokinetics: Absorption, distribution, and elimination

- Pharmacodynamics: Efficacy and toxicity of the drug

- Time-dependent: Efficacy depends on the time above MIC

- Concentration-dependent: Efficacy depends on peak concentration

- Bacteriocidal: More rapid killing and reduction of growth

- Bacteriostatic: Suppression of growth but no active killing --> Maybe due to relying on the immune system

- Penicillins

- Beta lactamase inhibitor combinations

- Cephalosporins

- Carbapenems

- Monobactams

- Vancomycin

- Mechanism of Action: Inhibits peptidoglycan synthesis by binding to penicillin binding protein and inhibits tetrapeptide linkage --> Cell lysis then occurs

- Rapidly bactericidal and time-dependent

1. Penicillin G (IV) and penicilin BK (PO) --> Narrow G+

2. Penicillinase resistant penicillins (nafcilin and dicloxacilin) --> G+ broad, especially Staph

3. Aminopenicillins (ampicillin) --> Narrow G+ and adds some G-

4. Carboxypenicillins and ureidopenicillins --> Narrower G+ and broad G- 

- None do enterococci

- Absorption: Good bioavailability, mostly IV/IM but some available PO (amoxicillin/penicillin)

- Distribution: Widely and 5-20% in CSF

- Metabolism: Minimal

- Excretion: Renal (unchanged)

- Time-dependent --> Alter dose but keep interval the same

- Concentration dependent --> Alter interval but keep the dose the same --> Same peak

- Usually altered for renal disease but also for severe hepatic disease too

- Hypersensitivity --> True anaphylaxis and cross reactivity with cephalosporins

- Thrombophlebitis

- GI distrubances

- Hematologic --> Leukopenia, etc

- Electrolyte disturbances --> Most common with carboxypenicillins (use ureidopenicillins instead

- Neurologic --> Reduce seizure threshold

- Interstitial nephritis

- Intrinsic: Within species (Klebsiella lactamase) --> Prevents drug from reaching site or inactivates drug

- Acquired: Resistance that develops --> Horizontally or vertically (hospitals)

- Mechanisms of resistance: Drug can't reach site, drug inactivated, target site altered, and efflux pumps

1. Drug becomes inactivated by bacterial B-lactamases

- Produce penicillinases and cephalosporinases also

2. Bacteria can alter the structure of the penicillin binding proteins

3. Can alter the outer membrane permeability (G-)

- Clavulanic acid

- Often used in combination with some penicillins

- Similar in structure to the bacterial beta-lactamases

- Inhibits some but not all beta-lactamases

- Prevents the destruction of antibiotic

- Enhances the spectrum and activity of the antibiotic

- Bacteriocidal and time-dependent

- None do Enterococci

1. 1st gen.: Cefazolin --> Broad G+ and narrow G-, mostly S. aureus!!

2. 2nd gen.: Cefuroxime --> Narrow G+ and broad G-

- Cephamycins: Cefoxitin --> Anaerobe activity, not really used clinically

3. 3rd gen.: Ceftriaxone --> Narrow G+ and Broad G- --> Good for penicillin resistant Strep.

4. 4th gen.: Cefepine --> Broad G+ and G- activity --> Good for Pseudomonas --> Don't always need that much activity

- Absorption: Lower bioavailability for PO so IV for severe infections

- Only cefuroxime available PO

- Distribution: Widely distributed, including CSF

- Metabolism: Minimal

- Excretion: Mostly renal (unchanged)

- Longer half life than penicillins!!

- Generally well tolerated

- Hypersensitivity possible --> Cross-reactivity with penicillin

- GI disturbances

- Hematologic

- Renal

- Nephrotoxicity

- Imipenem/cilastatin: Administered in combination because cilastatin prevents breakdown of impenem by renal dyhydropeptidases

- Bacteriocidal and time-dependent

- Broad spectrum: G+, G- and anaerobes

- Generally reserved for cases when strain is resistant to other penicillin drugs

- Resistant to hydrolysis but many B-lactamases

- Absorption: Only IV

- Distribution: Wide

- Metabolism: Minimal

- Excreted: Renal, highest concentrations in urine, and requires dose adjustment with renal dysfunction

- Hypersensitivity

- Seizures --> Lowers threshold

- GI distrubances

- Inhibits cell wall synthesis

- Bacteriocidal and time dependent --> Slower than penicillins and cephalosporins

- Activity: G+ aerobes including MRSA

- Uses: Strains resistant to penicillins, in patients unable to tolerate penicillins and 2nd line therapy for C. diff

- Absorption: Poor oral, only used PO for C. diff

- Distribution: Wide but not CNS

- Metabolism: Minimal

- Elimination: Renal excretion

- Monitor trough levels

- Infusion related effects --> Slow down infusion rate

- Hematologic

- Hypersensitivity

- Ototoxicity/Nephrotoxicity are rare

- Used clinically for over 30 years without resistance

- First vancomycin resistant enterococci (VRE) in Europe in the 80s

- Resistance due to increased clinical use and agricultural use

- Due to alterations in target site

- VISA/VRSA --> First appeared in 1996

- Aminoglycosides

- Tetracyclines

- Macrolides

- Clindamycin

- Quinolones

- Metronidazole

- Gentamicin

- Bacteriocidal and concentration dependent

- Mechanism: Passively diffuses through porins and oxygen dependent transport through membrane to bind 30S

- Reduced activity in anaerobic conditions and acidic environments

- Increased activity in combination with cell wall synthesis inhibitors

- Spectrum: G+ and G- aerobes, protozoa, and mycobacteria

- Absorption: Poor oral absoprtion

- Distribution: Only into extracellular space --> Hydrophillic

- Uses: In combination for most infections but alone for UTIs

- Metabolism: Minimal

- Elimination: Renal (unchanged)

- Nephrotoxicity: When concentrations are too high

- Ototoxicity

- Neuromuscular blockade

- Monitor peaks and troughs

- Post antibiotic effect: persistent suppression of bacterial growth following exposure to antibiotic

- Concentration dependent

- Cmax:MIC= 10:1

- Cmax: Peak drug concentration, must take into account protein binding

- Inhibit bacterial growth through synergy

- Penicllin: Inhibits cell wall synthesis

- Gentamicin: Inhibits protein synthesis

- Leads to increased bacterial killing

- Uses: Endocarditis and endovascular infections

- Drug cannot reach target site

- Drug inactivated

- Target site is altered

- Tetracycline and doxycycline

- Bacteriostatic and time dependent --> Concentrates intracellularly

- Mechanism: Reversibly binds 30S ribosome

- Spectrum: G+, G-, anaerobes, Lyme, Brucellosis, Cholera, Syphilis, Chlamydia, and other atypicals

- Use: Mild/moderate respiratory infections and Lyme disease

- Absorption: Good oral absorption but binds cations so absorption decreased by dairy and antacids

- Distribution: Wide but concentrates in bile, liver, kidney, spleen, skin, and bone

- Metabolism: Glucuronidation in liver

- Elimination: Excreted in urine and bile (Long half life)

- Photosensitivity

- Tooth/bone discoloration (children)

- GI disturbances

- Hepatotoxicity

- Renal toxicity

- Drug can't reach target site --> Efflux pumps

- Drug is inactivated by enzymes

- Target site altered 

- Azithromycin --> Bacteriostatic and time-dependent

- Concentrates intracellularly

- Mechanism: Reversibly binds 50S

- Spectrum: Broad G+, narrow G- and atypicals

- Azithromycin adds H. influenzae, Chlamydia, Mycoplasma, and Legionella activity

- Uses: Mild/moderate respiratory infections, alternative for patients with penicillin allergies and NOT used for blood, urine, or soft tissue infections

- Absorption: Good oral absorption but some food interactions

- Distribution: Distributes well, CSF too, but serum levels low because intracelllular concentrations of neutrophils and macrophages are high

- Metabolism: Liver and P450 inhibitor

- Elimination: Excretion in bile and urine --> Long half-life

- CYP3A4 substrate and inhibitor

- Erythromycin is the worst

- Leads to increased levels of amiodarone, digoxin, warfarin, statins, Ca channel blockers, carbamezapine and others

- Mostly alters with cardio drugs

- GI disturbances --> Nausea and vomiting

- QTc prolongation

- Drug cannot reach target --> Efflux pumps or decreased penetration into cell

- Drug inactivated by enzymes

- Target site altered

- Similar to macrolides

- Bacteriostatic and time dependent

- Mechanism: Reversibly binds 50S

- Spectrum: Broad coverage of G+ aerobes and G+ and G- anaerobes

- Uses: Pulmonary, pelvic/abdominal, and dental infections

- Alternative to patients allergic to penicillin

- Absorption: Good oral absorption, given IV or PO

- Distribution: Wide except CSF

- Metabolism: Oxidated in liver

- Elimination: Excreted in bile and urine

- GI disturbances --> Diarrhea and C. diff overgrowth

- Metallic taste

- Cross resistance with macrolides

- Drug inactivated by enzymes

- Target site is altered

- Levofloxacin and ciprofloxacin --> Four generations

- Bacteriocidal and concentration dependent

- Mechanism: Inhibits topoisomerase II + IV --> Inhibits DNA replication

- Spectrum: Moderate G+, broad G- and atypicals

- Use: G- infections, respiratory, urine, soft tissue, and bone/joint infections, atypical infections (Shigella, Salmonella, and Mycobacteria), inhalation anthrax exposure, gastroenteritis, and prostatitis

- Absorption: Excellent oral absorption, impaired by antacids and multivitamins

- Distribution: Wide

- Metabolism: Minimal

- Elimination: Renal (unchanged)

- Generally well tolerated

- GI disturbances

- CNS --> Headache and dizziness

- Rash

- Photosensitivity

- QT prolongation

- Hypo/hyperglycemia

- Tendon rupture

- Drug cannot reach target --> Efflux pumps

- Drug inactivated

- Target site is altered --> one step point mutation

- Increasing prevalence of resistance --> Widely used

- Bactericidal and concentration dependent

- Mechanism: Enters cell and reduced to cytotoxic product and damages DNA, RNA and proteins

- Spectrum: G+ and G- anaerobes and protozoa

- Use: C. difficile colitis (1st line), and other anaerobic infections below the diaphram

- Absorption: Excellent oral absorption

- Distribution: Wide and CSF

- Metabolism: Active metabolites from liver

- Elimination: Urine and feces --> Adjust for liver and renal dysfunction

- Generally well tolerated

- GI disturbances

- Metallic taste

- Disulfiram reaction with alcohol!!!

- Peripheral neuropathy

- Trimethoprim/sulfamethoxazole (Bactrim): Antifolate sulfa drugs

- Bacteriostatic

- Sulfonamids: Inhibits Dihydropteroate synthase by competing with PABA

- Trimethoprim: Inhibits dihydrofolate reductase

- Mechanism: Inhibits DNA synthesis

- Spectrum: G+ aerobes including MRSA, G- aerobes, Listeria, Shigella, and Pneumocystis jiroveci

- Uses: UTIs, PCP pneumonia, Stenotrophomonas, skin/soft tissue infections caused by S. aureus, and reported failure in abcesses and bacteremia

- Absorption: Good oral absorption --> PO or IV

- Distribution: Wide, moderate CSF and concentrates in urine

- Metabolism: Minimal

- Elimination: Renal excretion --> Competes with creatinine for excretion

- Patients may seem to show renal failure, but not truly renal failure

- Hypersensitivity: Common and can cause serious rashes

- Hematologic: Decreased WBCs, RBCs, and platelets

- Photosensitivity

- Crystalluria with acid pH --> Can cause renal failure

- Sulfonamides: Decreased cell permeability, overproduction of PABA, and production of mutant folate enzyme

- Trimethoprim: Decreased cell permeability, overproduction of dihydrofolate reductase, and production of mutant reductase enzyme

- Isoniazid

- Rifampin

- Commonly used in combination with other agents

- Resistance develops quickly

- Multi-Drug Resistant (MDR): Resistant to at least isoniazid and rifampin

- Extensively Drug Resistant (XDR): Resistance to at least isoniazid, rifampin, any fluoroquinolone and one second-line injectable drug

- Bacteriocidal

- Mechanism: Inhibits mycolic acid synthesis

- Spectrum: Only Mycobacteria

- Absorption: Good oral absorption

- Distribution: Widely distributed and CSF

- Metabolism: Acetylation by liver

- Elimination: Renal excretion

- Hepatotoxicity: 10-20% asymptomatic, most commonly 1-2 months after treatment

- Peripheral neuropathy: <20%, supplement with vitamin B6

- Skin reactions: Urticaria

- Bacteriocidal

- Mechanism: Blocks bacterial RNA polymerase

- Spectrum: Mycobacteria and G+/G- organisms

- Use: Mycobacterial infections and G+ bacterial infections

- Given in combination with other therapies

- Absorption: Good oral absorption

- Distribution: Lipophilic and variable CSF penetration

- Metabolism: Deacetylated to active form and induces P450 enzymes

- Elimination: Excreted through bile and enterohepatic recirculation

- CYP450 inducer

- Reduces levels of clarithromycin, fluconazole, protease inhibitors, other HIV drugs, cardiovascular agents, and others

- Rash

- GI distrubances

- Hepatotoxicity

- Orange body fluids

- Flu-like syndrome

- Amphotericin B --> Fungicidal

- Mechanism: Binds egosterol, leading to increased membrane permeability

- Spectrum: Yeasts (Candida, Cryptococcus, histoplasmosis, and blastomycoses) and molds (Aspergillus and mucormycosis)

- Use: Gold standard of antifungals

- Absorption: IV only

- Distributed: Accumulates in tissues, very lipophilic

- Metabolism: None

- Elimination: Excreted in bile and urine minimally --> Long half-life

- 3 lipids have been added to formulation so dosing is different for all!!

- Toxicity usually limits use --> Lipid products help decrease nephrotoxicity through macrophage endocytosis

- Nephrotoxicity: Glomerular or tubular due to cytokine release

- Infusion fever reactions: Chills, fever and tachypnea

- Electrolyte disturbances: K and Mg wasting

- Hematologic disturbances

- Hepatotoxicity

- Fungistatic

- Fluconazole, itraconazole, and voriconazole

- Mechanism: Inhibits fungal P450 enzymes

- Metabolism: Metabolized in the liver to different extents

- Adverse effects: Hepatotoxicity

- Azole

- Spectrum: Candida and Cryptococcus species

- Use: Mucocutaneous candidiasis, suspceptible invasive candidiasis, and 2nd line for Cryptococcal meningitis

- Resistance: Common in C. glabrata --> Dose dependent susceptibility

- Absorption: IV and PO

- Distribution: Wide including CSF

- Metabolism: CYP450 inhibitor --> Less than other azoles

- Elimination: Urine and bile

- Generally well tolerated

- GI effects

- Elevations of LFTs

- Reversible alopecia

- QT prolongation

- Caspofungin

- Fungicidal

- Mechanism: Inhibits fungal cell wall synthesis by inhibiting glucan synthase

- Spectrum: Broad Candida coverage and Aspergillus

- Use: Invasive candidiasis, and 2nd line for invasive Aspergillus

- Absorption: IV only

- Distribution: Widely distributed

- Metabolism: Hydrolysis and N-acetylation in the liver

- Elimination: Excreted in bile, feces, and urine

- Generally well tolerated

- Hepatotoxicity (rare)

- Nephrotoxicity (rare)

- Hypersensitivity (rare)

- Increased liver enzymes

- Expensive treatment for Candida

- Mechanism: De-aminated to 5-FU (chemo) within the cell and inhibits DNA and RNA synthesis

- Spectrum: Candida and Cryptococcus species

- Use: Combination therapy with amphotericin B

- Adverse Effects: Rash, hepatotoxicity, and myelosuppression (5-FU)

- Resistance: Used in combination to avoid resistance

- Absorption: Rapid oral absorption

- Distributed: Widely distributed including CSF

- Metabolism: Minimal

- Elimination: 90% excreted unchanged in urine 

- Must monitor levels in patients with renal dysfunction

- Must watch 5-FU levels for toxicity!!

- Gram-positive, club shaped with red metachromatic granules

- Aerobic, non-motile and catalase-positive

- Toxigenic and non-toxigenic strains possible --> Classic A-B exotoxin --> Expressed with low Fe levels

- Humans are only reservoir --> Asymptomatic carrier in URT, GI, UGT, and skin

- Most people in the US are vaccinated --> Don't always get boosters so elderly at risk

- Transmission: Respiratory droplet and skin contact

- Local attachment to epithelial cells in the pharynx

- Replication and release of toxins in the pharyns

- Incubation: 2-4 days

- Symptoms: Pharyngitis with exudate and low-grade fever

- Pseudomembrane including necrotic tissue develops

- Severe cases: Neck swelling and systemic complications

- Children: Pseudomembrane can grow or become dislodged to block trachea

- Entry through skin breaks

- Papule develops into non-healing ulcer

- Grayish pseudomembrane may also result

- Clinical presentation

- Gram stain (G+) and granule staining

- Culture on Loeffler's medium and Tellurite agar

- Testing for toxin: Elek test and PCR performed

- Treatment: Administration of antitoxin and penicillin/erythromycin treatment

- Prevention: DTaP and Tdap vaccines and Td boosters every 10 years

- Non-diphtherial corynebacteria

- Can also cause disease!!

- G- rod in pairs

- Usually motile, obligate aerobe

- Oxidase + and non-lactose fermenter

- Virulence: Capsule in some species and antibiotic resistance

- Ubiquitous in the environment --> Grows in water

- Opportunistic pathogen --> Not common flora

- Risk groups: Burn and cystic fibrosis patients, urinary cathers, immunosuppression, or broad-spectrum antibiotics

- Responsible for ~10% of hospital infections

- Capsule, pili, and flagella

- Exotoxins: Toxin A, hemolysis, phospholipase C, pyocyanin (pigment), proteases, exoenzyme S, and leukocidin

- Infection sites: Ear, eye, skin, respiratory tract, UTI and CNS infections, endocarditis and bacteremia

- Lac - on MacConkey Agar

- Produces pyocyanin --> Green colored on agar

- Smells like grape kool-aid

- Also need susceptibility testing too!!

- Treatment: Antibiotics and combination therapy

- Prevention: Infection control

- Prophylactic use is NOT recommended

- G+ coccobacilli in pairs or short chains

- Mobile --> Characteristic tumbling

- Facultative anaerobe and intracellular pathogen

- Grows in broad temperature ranges!!

- Ubiquitous in environment --> ~1,600 cases/year

- Transient colonizer of humans

- Transmission: Contaminated food and from mother to fetus

- Serious disease: Neonates, elderly, pregnant women, and complement deficiency

- Attachment to receptors on GI epithelium (enterocytes and M cells) --> Travels into Peyer's patches

- Phagocytosed but escapes phagolysosome by secreting Listeriolysin O

- Replicates within the cytoplasm

- Forms actin tail to travel to neighboring cells --> Dissemination

- Health adults: asymptomatic flu-like illness with or without GI symptoms

- Pregnant women: Flu-like illness but meningitis possible

- Fetus and newborn are at high risk --> Meningitis

- Immunocompromised and elderly: Higher risk of meningitis

- Diagnosis: Isolation of organism in CSF --> Specific tests

- Treatment: Ampicillin/penicillin with gentamicin in CNS infections

- Prevention: Safe food handling and consumption

- No vaccine available

- Non-lobar pneumonia --> Diffuse patchiness

- Chlamydia, leigonella and mycoplasma

- Below glottis

- Bronchitis, pneumonia and bronchiolitis

- Above the glottis

- Pharyngitis, laryngitis, otitis, tonsillitis, rhinitis, and sinusitis

- Infection or inflammation of the lung most often caused by infectious organisms

- Community acquired vs. hospital acquired

- Typical vs. atypical

- Other: Aspiration, post-viral, and special at-risk populations

- Streptococcus pneumonia

- Viruses: Influenza virus, adenovirus, parainfluenza virus

- Atypical: C. pneumoniae, L. pneumophilia, and M. pneumoniae

- Haemophilus influenzae

1. Chlamydiae --> Chlamydia trachomatis

2. Chlamydophila --> C. pneumoniae and C. psittaci

- G-, obligate intracellular parasite, and no peptidoglycan cell wall

- Non-culturable --> Replications intracellularly

- Elementary body: Taken up by endocytosis

- Becomes active reticulate body within cell

- Reticulate bodies replicate

- Reticulate bodies return to elementary body state

- Elementary bodies released from cells

- Human pathogen only

- Transmission: Close contact, usually sexual

- >19 serovars --> Different diseases

- Syndromes: Trachoma, STI, adult conjunctivitis, and perinatal acquired conjunctivitis and pneumonia

- Conjunctivitis: Inflammation of the conjunctiva (membrane lining of eyelid)

- Keratitis: Inflammation of the cornea

- Trachoma

- Active trachoma: Occular infection, conjunctival inflammation and follicle formation

- Cicatricial disease: Eyelid scarring, trichiasis (ingrown eyelashes), and corneal opacification and blindness

- Common cause of blindness in developing countries

- >80 million with trachoma, >7 million have trichiasis, and >1 million have blindness

- Women: vaginitis, endometriosis, salpingitis, and oophoritis --> Can lead to PID and infertility

- Men: Lymphogranuloma venereum (LGV) in men who have sex with men, proctitis, and urethritis

- Men and women are often asymptomatic

- Infects epithelial cells, replicates and induces inflammation

- Diagnosis: NAATs necessary

- Treatment: Azithromycin, treat sexual contacts, test for other STIs and treat neonates born to infected mothers

- Prevention: Barrier protection during sex

- Multifocal, patchy consolidation throughout lungs

- Cause of atypical pneumonia

- Transmission: Person-to-person via respiratory droplets

- Treatment: Azithromycin

- Causes atypical pneumonia

- Transmission: From exotic birds such as macaws, also from poultry

- Treatment: Azithromycin

- G- rod

- Facultative intracellular parasite

- Grows in freshwater amoeaba in nature, macrophages, monocytes, and epithelial cells

- Forms biofilms in human-made water systems

- Multiple serogroups

- Diagnosis: Special culture conditions with Fe, cystine, and charcoal

- Transmission: Inhalation of contaminated water --> No human-to-human transmission

1. Entry via endocytosis --> Various mechanisms including secretion systems

2. Phagosome does not fuse with lysosome --> Evades killing

3. Organisms replicates in vacuole and produces cytotoxic enzymes 

- Replicates in macrophages --> Stimulates inflammatory response

- Organism produces various enzymes and exotoxins

- LPS --> Endotoxin!!

- Cell mediated response contributes to pathogenesis

- Most commonly affects adults

- Legionnaire's Disease: More severe disease, presents as pneumonia --> Decreased rate but increased mortality

- Pontiac Fever: Less severe disease (mild flu) --> Increased rate but decreased mortality

- Caused by the same pathogen --> Unclear why this is possible

- No cell wall --> Gram stains don't work

- Membrane containing sterols --> Special media with sterols and lipids to grow

- Strict aerobe --> Replications extracellularly

- Strict human pathogen --> ~ 2 million/year (5-15 y.o.)

- Common colonizer in the URT and LRT --> Asymptomatic carrier

- Transmission: Respiratory droplets --> VERY contagious

- Treatment: Cell wall targeting antibiotics don't work!!

- Presentation: Atypical pneumonia

- Incubation: 2-3 weeks --> tracheobronchitis, low-grade fever, malaise, and headache

1. Adhesion binds ciliated epithelium in lungs

2. Bacteria produces H2O2 and cold agglutinins --> Cells die

- Kills off the mucociliary escalator --> Persistent cough

- Atypical pneumonia: "walking pneumonia" --> Patchy bronchopneumonia

- Diagnosis: Serology and PCR

- Treatment: Erythromycin

- Prevention: Not much... No vaccine

- Commonly caused by Herpes, Syphilis, and Chancroid

- Syphilis: Single lesion, clean base, without pain and non-tender bilateral lymphadenopathy

- Chancroid: Multiple lesions, dirty base with pain and tender unilateral lymphadenopathy

- Herpes: Multiple lesions, clean base with pain and tender bilateral lymphadenopathy

- Spirochete --> Detected via darkfield mycroscopy and serology

- Treatment: Penicillin G

- More common in younger men --> Homosexual men

- Equally symptomatic in men and women

- Presents as a chancre --> Resolves even without treatment

- Can disseminate to secondary

- Treatment: Penicillin

- Systemic disease --> Maculopapillary rash and lymphadenopathy

- Rash includes the palms and soles of the feet

- Does not develop in everyone

- Condylomata lata: Lesions on the genitalia

- Will recover without treatment but lesions contain organisms

- Early latent --> 1 year after symptoms --> Can have sudden outbreaks of rash and highly contagious!!

- Late latent --> Not really contagious and no presence of organisms

- Can present months or decades after secondary

- Due to disseminated disease

- Late benign disease --> Granulomas/gummas in cartilage, bone, liver, heart and brain

- Neurosyphilis

- Argyll-Robertson pupil is common: Pupils constrict with accommodation but not to light and pupils are small and irregular

- Loss of coordination

- Abnormal gait

- Passed from mother to fetus

- Shows up weeks to months after birth

- Symptoms: Sniffles/nasal discharge contaning organisms and rash

- Rash can be either pustular or bullous

- Bone, eye, ear, and tooth malformations

- Eye: Anterior uveitis and interstitial kratitis

- History and physical exam

- Non-specific serology test followed by specific serology test

- Non-specific (VDRL and RPR)

- Specific (FTA-ABS, TPHA, and MHA-TP)

- Penicillin

- Patient with penicillin allergy --> Can use erythromycin, doxycycline or tetracycline instead but ALOT less effective

- Patient's with neurosyphilis, congenital syphilis and pregnant women should be desensitized and given penicillin

- Follow-Up Testing: Should see a drop in titer --> 4-fold decrease in non-specific antibodies if treatment worked 

- Occurs in 1/3-2/3 of patients

- Acute febrile reaction --> Fevers, chills, arthralgias, headache and more prominent lesions

- Due to release of treponemal consituents

- Must warn patients about this!!

- Not seen in the US

- Bejel

- Yaws

- Pinta

- May cross-react and give a false positive for syphilis

- Pathogen causing chancroid

- Incubation: 3-10 days --> Soft painful chancre

- Multiple lesions are common

- Painful inguinal lymphadenitis

- History and physical exam

- Gram stain of exudate --> Suggestive of infection

- Culture not generally available

- Other tests not really available either

- Treatment: Azithromycin, ceftriaxone, and ciprofloxacin

- Transmitted from animals to humans

- Directly transmitted

- Vector transmitted --> Insects, mice, fleas, etc

- Most common: Lyme disease

- Most life-threatening: Rocky Mountain Spotted Fever

- G- cocci but do not stain well

- Obligate intracellular parasites

- Symptoms: Fever, headache, rash and multi-system involvement

- Symptoms due to replication and death of vascular endothelial cells

- Ex. Rocky Mountain Spotted Fever and Typhus

- Rash: Usually several days after fever and photosensitivity, includes palms and soles of the feet

- Common in chlidren --> Often not diagnosed because it's rare

- Cause of Rocky Mountain Spotted Fever (RMSF)

- Vector: Dog tick

- Reservoir: Dogs, rodents, and ticks

- Location: SE states and central US

- Events: R. rickettsii transmitted to human through bite, bacteria replicate in endothelial cells, rash may appear 2-6 days after and may result in multi-organ disease

- Symptoms: Severe headache, high fever, and rash

- Rash: Begins on hands and feet and spreads inward

- Treatment: Doxycycline --> Fatal without treatment!!

- Cause of epidemic typhus --> Common in developing countries with low hygiene

- Human lice (Vector, reservoir and host)

- Symptoms: incubation 1-3 weeks, flu-like symptoms, fever, headache, chills, and rash

- Rash: Begins on trunk and extends peripherally but spares palms and soles

- Often presents with escar

- Can cause coma and vascular collapse without treatment but not as fatal as RMSF

- Treatment: Doxycycline

- Causes endemic/murine typhus --> 20-80 cases/year in US

- Vector: Fleas

- Reservoir: Rats

- Symptoms: Fever, headache, and rash

- Rash: Restricted to chest

- Often presents with escar

- Growth is difficult but possible

- Serological tests can be done but not generally

- Typical presumptive diagnosis based on presentation and history

- Treatment: Doxycycline

- Prevention: Dress appropriately when outside, avoid exposure, do tick inspections

- Tick must be attached for 24-48 hours in order to transmit disease!!

- G- coccobacillus bacteria causing Q fever --> ~130 cases/year in the US

- Obligate intracellular pathogens --> Difficult to stain

- Risk factors: Working with animals

- Transmission: Inhalation of aerosols containing contaminated urine, feces and body fluids

- ~50% of patients asymptomatic

- Symptoms: Rapid onset of fever (1-2 weeks after), severe headache, cough, flu-like symptoms without rash

- Resolves without treatment in ~50%

- 30-50% go on to develop pneumonia

- Abnormal liver tests common --> Can lead to hepatitis

- ~5% of patients go on to develop chronic Q fever

- Diagnosis: Serology

- Treatment: Doxycycline for severe cases, otherwise nothing

- Prevention: Avoid exposure, good hygiene, disinfection, avoid unpasturized milk, and screen farm animals

- Vaccines available in other countries --> NOT in US

- G- obligate intracellular pathogen --> Forms morulae inside monocytes

- Vector: Lone-star tick

- Reservoir: White-tailed deer

- Human Monocytic Ehrlichiosis (HME)

- Usually acute but can become chronic

- Incubation: 1-2 weeks

- Symptoms: Flu-like symptoms with leukopenia, thrombocytopenia, and elevated ALT/AST

- Rash seen in ~30% of patients

- Similar to RMSF in presentation and location

- Disease severity: ~50% of patients require hospitalization --> Mortality of 2-3%

- Risk factors: Old age and immunocompromised

- G- obligate intracellular pathogen --> Forms morulae in granulocytes

- Causes Human Granulocytic Anaplasmosis (HGA)

- Vector: Ixodes scaplaris (tick)

- Reservoir: Small mammals

- Incubation: 1-2 weeks

- Usually acute  but can become chronic

- Symptoms: Fever, flu-like symptoms with leukopenia, thrombocytopenia, and elevated ALT

- Rash uncommon

- Severity of disease: ~50% require hospitalization and <1% mortality

- Similar presentation and location as RMSF and HME

- Risk factors: Old age and immunocompromised

- Diagnosis: PCR

- Treatment: Doxycycline

- Prevention: Avoid ticks, tick inspections, etc

- Spirochete causing leptospirosis

- Transmission: Exposure to contaminated water

- Entry: Ingestion or through skin breaks

- Symptoms: Variable with abrupt onset

- Incubation: 2-4 days

- Some recurring disease is possible --> Weil's disease is most severe

- Can cause endothelial cells demage

- Treatment: Usually self-limiting in healthy patients, treated with doxycyclin or penicillin otherwise

- Prevention: Avoid exposure and vaccinate animals

- No human vaccine

- Motile (flagella) spirochete causing Relapsing fever

- Can either be tick or louse born

- Tick-borne (endemic): Tick --> Rodent in West

- Louse-born (epidemic): Human lice --> War regions/refugee camps

- Incubation: ~7 days

- Symptoms: 3 day fever that goes away for the next 7 days

- Re-infection possible due to antigenic variation

- Usually resolves after 1-4 episodes

- Higher motality in LBRF

- Diagnosis: Lab tests difficult and slow --> Presentation/history

- Treatment: Empirically with tetracylcin

- Prevention: Avoid exposure with vectors

- All G- rods/coccobacilli

1. Brucella spp. --> Brucellosis via pigs, cattle, goats and sheep --> From dairy products

2. Francisella tularensis --> Tularemia via rabbits, deer, and ticks --> From antimal tissue contact

3. Yersina pestis --> Plague via fleas from rodents

4. Pasteurella multocida --> Cellulitis via cat and dog bites (normal flora) 

- Viral: Deer Tick Virus --> Rare cause of fatal encephalitis

- Rickettsial

- Ehrlichia

- Anaplasma

- Lyme

- Relapsing Fever

- Tularemia

- Babesiosis

- Spirochete that causes Lyme disease in the US

- B. garinii and azfelii are causative agents in Europe

- Incidence of Lyme increased in this area due to deforestation and increased prevalence of deer

- Ticks got to the area on migrating birds

- Ixodes scapularis --> New England

- Ixodes pacificus

- Ixodes ricinus

- Ixodes persulcatus

- Ixodes scapularis also carries anaplasma, causing HGA, and Babesia microti, causing Babesiosis

- Adult ticks lay eggs in the fall

- Eggs hatch in the spring

- Larvae attach and feed on rodents

- Spirochete grows in within the white footed mouse

- Larvae obtain spirochete when they bite mouse

- Ticks now carry spirochete

- Ticks can bite humans for next meal and transmit spirochete to human

- Erythema migrans: Classically represented as bullseye

- Usually presents as solid red rash bigger than a tennis ball and smaller than a basketball

- Usually found behind the knee, lower back, groin or armpit

- 25% of times the rash can disseminate to develop multiple lesions

- Even though it looks like cellulitis, IT IS NOT!!

- Erythema migrans can occassionally become necrotic

- Other symptoms: Flu-like symptoms, arthritis, carditis, and neurological symptoms

- Arthritis usually presents weeks to months after bite

- Carditis --> 3rd degree heart block

- Meningioencepalitis

- Bell's Palsy --> Usually early and bilateral!!

- Radiculitis

- Peripheral neuropathy --> Uncommon

- Encephalopathy

- Two step test

- Begins with ELISA --> Then western blot for Lyme specific proteins

- Not very useful --> Lots of false positives

- False positives with lupus, RA and syphilis also

- Avoid use with arthralgia, myalgia, fatigue, and palpations --> Non-specific complaints

- Western blot: Tests IgM and IgG for proteins

1. Erythema migrans

2. Early disseminated Lyme

3. Lyme arthritis

4. False positives possible with other conditions --> Lupus, RA and syphilis

- Oral: Doxycyclin, amoxicillin, erythromycin and penicillin

- IV: Ceftriaxone and penicillin

- Others: Azithromycin and cefuroxime

- Treatment for Erythema migrans: 10 days of doxycyclin therapy

- Advese effects: Photosensitivity!!

- Treat empirically even without positive test!!!!

- No change in status with placebo and antibiotic patients

- Cause of chronic Lyme is not treated by antibiotics!!

- No evidence that spirochete actually persists

- Keep out of high grass

- Wear proper clothing --> Light clothing (see ticks)

- Use DEET on lower legs

- Tick checks

- Properly remove ticks if found

- Avoid prophylactic antibiotics

- Still only 3% chance of getting infected when bit by a tick

- No longer a vaccine

1. Is it an infection?

2. Is it bacterial?

3. How sick is the patient (IV vs. PO)?

4. How quickly does patient need to be started on treatment?

5. What are the consequences if you make a mistake?

6. Site of infection --> Endogenous vs. exogenous

7. What are the most common infections in this host?

8. Host: Age, medical history, social history, etc

9. Bacteriocidal vs. bacteriostatic

10. Distribution of drug of choice into infection site

- Need bacteriocidal agent!! --> Vancomycin up front

- S. aureus most common --> High resistance!! 

- Anaerobes possible --> Patients with gingivitis and poor dental hygiene

- S. epidermidis and G- possible with valve replacement

- S. pneumonia and atypicals possible

- 3rd gen cephalosporin (ceftraxone) and azithromycin

- Atypicals: Fluroquinolone or macrolide

1. Levofloxacin is better than azithromycin --> Higher serum levels for seriously ill patients

2. G- possible (E. coli & Klebsiella) in patients with diabetes

- Don't treat lung infection from Klebsiella with gentamicin --> Poor penetrance into lungs and poor activity with acidic pH and anaerobic conditions

3. HIV+ with CD4 of 25 --> S. pneumonia and fungal infections (very severe!!)

- CD4 of 500 --> S. pneumo and mycobacteria but NOT fungal

- Most common: S. pneumoniae and N. meningitidis in 18-50 y.o --> Different for different age groups

- Treatment: Ceftriaxone and vancomycin to cover possible resistance --> Treat quickly!!!

1. Immunosuppresion/lupus: Listeria and G- causes can happen --> Vancomycin

2. Shunt for hydrocephalus: S. epidermidis and shunt associated bacteria --> Vancomycin

- Higher dose of ceftriaxone (2 g) and shorter interval (12 hours) --> Needed to get proper MIC in CSF

- Patients sometimes come in without meningismis (neck stiffness) --> Can just disseminate and progress that quickly!!

- Commonly caused by group B strep and S. aureus

- Oxacyclin/penicillin or ceftriaxone therapy

- Ulcers re-occur commonly --> Increased resistance with every re-appearance

- Strep and Staph still cause early reoccurances but others can come in afterwards

- Empiric: Treating for your best guess

- Definitive: Adjustment of therapy due to results of cultures/serolgy

- Prophylactic: Used in prevention of disease --> Common peri-surgically

- Always consider resistance --> De-escalate treatment whenever you can!!!

- Usually caused by G- bacilli/rods --> Often motile (E. coli)

- Determined by finding bacteria and leukocytes in urine

- Treatment: Levofloxacin because fluroquinolones are good against G- bacteria

- If reccurence occurs, prophylactic treatment can be used if reccurrence is situational

- Helminths

- Nematodes (Roundworms)

- Cestodes (Flat worms)

- Trematodes (Flukes)

- Transmission: Oral, inoculation, and direct penetration through skin

- Stage transformation: Transcriptional activation

- Adult (definitive) vs. Larval (Intermediate)

- Enormous variation in clinical presentation

- Most infections are asymptomatic

- Local vs. systemic effects

- Diagnosis: Visualize parasite in samples, clinical syndrome and PCR and DNA probes

- Treatment: Ranges from highly effective to no treatment

- Tissue protozoan parasite --> Toxoplasma gondii

- Worldwide problem --> Not so much in the US

- Seroprevalance >50% at adolescence in Western Europe, Africa, South and Central America

- Only 14-27% seroprevalence in the US

- Infection rate increases with age and differs regionally

- Oocytes are ingested by mice or small rodent

- Pseudocyst grows in the tissues of the mouse

- Mouse eaten by cat --> Undergoes sexual cycle in cat

- Cats excrete occytes in feces

- Pseudocysts can either be ingested from undercooked or raw meat

- Oocytes can be transmitted through feces

- Become tachyzoites in human host

- Tachyzoites infect the liver cells

- Infected macrophages distribute tachyzoites throughout the body

- Pseudocysts develop in the tissues as a response to the acquired immunity

- Infections: Brain lesions, chorioretinitis, lyphadenitis and hepatitis

- Ingestion of oocytes: Poor hygiene, contaminated water, contact with contaminated soil, and close contact with cats

- Ingestion of tissue cysts: Raw or uncooked lamb, beef or pork

- Also transmitted from goat, deer, bear, moose, elk, and kangaroo meat

- Shed by cats in feces

- Excreted for 7-20 days after infection of cats

- Up to 10 million shed in a day

- Must sporulate in environment --> Takes 1-5 days

- Viable for up to 16 months in the soil

- Oocyst --> Contains two sporocysts containing four sporozoites

- Sporozoites actually infect body

- Hallmark of active infection

- Present in either primary or reactivated infections

- Must invade into cells

- Invades contiguous cells or is phagocytosed

- Transported to other areas in the body

- Protected by the parasitophorous vacuole (food vacuole)

- Can be up to 200 mm and contain 3,000 bradyzoites (organisms)

- Forms 1 week after infection

- Probably viable throughout host's life

- Grows in brain, eye, heart muscle and skeletal muscle

- Bradyzoites are periodically released from cyst --> Small inflammatory reaction and tissue destruction

- Causes more severe symptoms in immunocompromised patients

- Parasites replicate and cause cell rupture without antibody production to infection

- Antibody production and binding to infected cells induces apoptosis

- Symptomatic in only 10-20% of people

- Incubation: 7-17 days

- Symptoms: Fever, lympadenopathy, myalgias, stiff neck, headache, and anorexia

- Rash, arthralgias and hepatomegaly are possible but less commmon

- Immunocompromised patients: Reactivation, encephalitis is most common but lung, retinal and heart infections are possible

- IgM antibodies are usually absent in immunocompromised patients

- Reactivation of in utero infection --> Mid 20s-30s

- Bilateral, old scars, involvement of macula

- 25% of posterior uveitis in the US --> 85% in Brazil

- Acquired disease is actually more common

- Retinochoroiditis with unilateral, painless, and focally necrotic retinal lesions

- Symptoms: Blurred vision, photophobia, and scotoma

- Newborn: Hydrocephalus, chorioretinitis, and intracerebral calcifications --> Highly variable symptoms, often missed

- Congenital: Primarily neurologic --> Retinochoroiditis, CSF problems, anemia, seizures, intracranial calcifications, hydropcephalus, microcephalus, and fever

- Isolate organism from culture

- Histology and immunoperoxidase staining

- PCR --> Crucial for intrauterine diagnosis

- Serology --> IgG and IgM levels but IgG is life-long so alone is useless

- Brain biopsy very uncommon but possible

- Brain scans --> Ring enhancing lesion!! 

- Protozoa in the order of Kinetoplastida

- Live in macrophages --> Intracellular amastigotes

- Promastigotes: Extracellular in sandfly gut

- Visceral, cutaneous, and mucocutaneous types

- Sandfly: Breeds in cracks in house walls, trash, and piles of rubble

- 2 million cases world wide (endemic)

- Reservoirs: Dogs, rodents and other small mammals

- Affects primarily children and young adults

- Risk factors: Malnutrition and HIV

- Pathogenesis: Replicates in quiescent macrophages but killed by activated macrophages --> Th1 immune response initiated via g-interferon and IL-12

1. Human Stages

- Sandfly takes blood meal from human

- Promastigotes phagocytosed by macrophages

- Become amastigotes --> Multiple

- Sandfly takes another blood meal from hum and ingests amastigotes

2. Sandfly Stages

- Ingestion of parasitized macrophage

- Amastigotes transform back into promastigotes

- Promastigotes divide and migrate to salivary gland

- Sandfly takes another bite

- Leishmania donovani

- Kala-azar --> Hindi for black sickness/fever

- Amastigotes disseminate to liver, splee, and bone

- Symptoms: Hypergammaglobulinemia, hepatosplenomegaly, weakness, fever, and pancytopenia

- Protective Th1 response is reduced or absent --> No DTH response to leishmanin skin test

- Cannot clear infection --> Cell death occurs

- Incubation: 3-8 months

- Complications: Bleeding, secondary bacterial infections, sepsis, edema and possibly death

- Post-kala azar derman leishmaniasis (PKDL): Relapse of disease in 2-20%, responds to treatment

- Demonstration of amastigotes in tissue (Giemsa stain)

- Isolation of Leishmania in culture

- Bone marrow aspirate --> Easiest but less sensitive

- Splenic aspirate --> Difficult and dangerous but most sensitive

- Leishmania tropica

- "Pizza-like" lesion --> Mixed acute and chronic inflammatory response

- Begins as papule --> Ulcerates --> Shallow and well defined

- Th1 response leads to scar formation and immunity

- Incubation: 2 weeks to several months

- Satellite lesions possible

- Secondary Staph or Strep infections may occur --> Open ulcer

- Diagnosis: Biopsy the border of lesion or PCR

- Leishmania braziliensis

- Prevalent in Central and South America

- Hematogenous or lymphatic dissemination of parasite

- Caused by members of Vianna subgenus

- Disseminates from skin to naso or oropharynx

- Usually occurs several years after CL in <5%

- Cure rates of 10-63% for advanced disease with antimony drugs

- Avoid areas where vector is found

- Spray homes with insecticides

- Use insecticide-treated bednets and curtains

- Vaccine development in progress

- Chagas' Disease --> Caused by Trypanosoma cruzi

- 16-18 million people are seropositive in Latin America --> Bolivia has highest rate of seroprevalence

- Most cases from central and southern Brazil

- 100,000 infected people in US --> Most don't know!!

- Reservoirs: Dogs, cats, guinae pigs and peridomiciliary rodents

- Vectors: Reduviid bugs

- Transmission: Congenital, blood transfusions, contaminated food, and laboratory accidents

- Trypomastigote ingested by human

- Turns into amastigotes in tissues

- Excreted in feces

- Ingestion of amastigotes by vector

- Turns to epimastigote in midgut of reduviid bug

- Epimastigotes multiply --> Turns to metacyclic trypomastigote

- Metacyclic trypomastigote becomes infective

- Acute: Mostly asymptomatic, 10-20% with non-localizing febrile syndrome, and <5% have severe illness with acute heart failure and meningoencephalitis

- Most severe in children

- Anemia, lymphocytosis, and modest increases in ALT/AST are common

- Chagoma: Inoculation granuloma/Romana's Sign --> Bipalpebral, unilateral chronic edema of the eye with bug feces rubbed in eye --> Edema lasts days to weeks

- Indeterminate Phase: Asymptomatic stage

- Chronic Disease --> Cardiomyopathy and Megasyndromes (megaesophagus and megacolon)

- Giema stained thick and thin blood smears

- Trypomastigotes in CSF, pericardial fluid, biopsies and bone marrow

- Xenodiagnosis for indeterminate or chronic

- Serology via ELISA --> IgG serologies

- Serology false positives due to syphilis, Leishmania, and malaria

- Prevention: Education, bug and nest control, and proper home construction

- African sleeping sickness

- Trypanosoma brucei rhodiense --> Eastern Africa

- T. brucei gambiense in Western and Central Africa

- Vector: Tsetse fly

- Symptoms: Chancre at site of infection, fever, rash, headache, lymphadenopathy, and altered mental status

- Incubation: 2-3 weeks

- Invades lymphoid-macrophage system

- Late symptoms: Anorexia, weight loss, lassitude, fatigue, stupor, coma and death

- Diagnosis: History, clinical findings, and demonstration of trypanosomes in Giemsa-stained blood smears

- Only Anopheles mosquitoes can transmit --> >60 species and exceptionally diverse

- Malarial parasites: P. vivax, P. ovale, P. malariae, P. falciparum, and P. knowlesi

- Other modes of transmission: Vertical, blood transfusions, needles sticks and sharing needles

- ~500 million cases/year --> ~800 thousand deaths/year

- Sickle cell anemia/trait, Thallassemia and P. falciparum immunity

- Duffy antigen negativity and P. vivax immunity in West Africa

1. P. vivax --> Benign tertian, everywhere except Western Africa --> Dormant stage, relapsing, sulfa drug resistance, 12-14 day incubation, 48 hour fever cycle and requires Duffy antigen

2. P. ovale --> Benign tertian, only West and Central Africa, dormant stage, relapsing, low risk of death, minimal resistance, 12-14 day incubation, 48 hour fever cycle and similar to P. vivax

3. P. malariae --> Quartan, tropical areas, no dormant stage, chronic but never relapsing, minimal resistance, 34 day incubation, and 72 hour fever cycle

4. P. falciparum --> Malignant tertian, tropical areas, no dormant stage, acute illness without relapses, kills millions, high resistance 12-24 day incubation, and 48 hour asynchronous fever cycle

5. P. knowlesi --> SE asia only, no dormant stage, acute and never relapsing, low risk of death, 12-14 day incubation, and 24 hour fever cycle

- Non-specific malaise

- Paroxysmal fever vs. intense sweating --> Abrupt onset of chills/shaking and high fever with headache and diarrhea

- Varying patterns of febrile and afebrile stages

- Uncomplicated malaria: Fever and melaise

- Complicated malaria: Hemolytic anemia, severe hypoglycemia, occlusion of microcirculation, and cerebral malaria

- Treatments can further lower blood sugar via insulin spike!!

- Long term: Growth failure/stunting, impaired mental development, and immunocompromised state

1. Schizogony: Makes schizonts in humans (7 days)

- Sporozoites injected into human by female mosquito

- Migrates to liver to infect hepatocytes --> Takes about 20 minutes

- Becomes either hypnozoite (dormant) or merozoite

- Micromerozoites are released into circulation

- Merozoites invade RBCs

- Merozoites replicate --> Burst out of RBC (Fever)

- Merozoites become male or female gametocytes

- Gametocytes taken up again by female mosquito

2. Sporogony: Makes sporozoites in mosquito (10-14 days)

- Mosquito injects gametocytes (needs both male and female)

- Zygote results --> Invades gut of mosquito --> Oocysts

- Oocysts migrate to salivary glands and form sporozoites

- Sexual: Genetic recombination --> Diversity!!

- Asexual: Continuous random variation --> Evolution of cell surface antigens and evasion of the immune system

- 8-amino quinolines --> Inhibit liver infection

- Chloroquine, amodiaquine, quinine, mefloquine, etc --> Inhibits replication in RBCs

- SP causes a brief increase in gametocytes --> Interesting side effect

- Vaccines: Sporozoite, merozoite, and gametocyte vaccines in development

- Sickle cell trait, Thallassemia, and duffy antigen negative

- Resistance is rarely complete --> Strain and species specific 

- Depends on continuous exposure!! --> Transient

- Immune system can learn to tolerate parasites even when unable to eliminate --> Tolerates symptoms

- Microscopy is still gold standard --> Blood smears

- Rapid diagnostic assays (dipsticks) --> HRP2 antigens, etc

- PCR --> Accurate but expensive!!

- Clinical diagnosis but very innacurate! 

- Thick smear: Stacked RBCs, lysed with methanol and stained for pathogens --> Sensitive but cannot speciate or quantify intesity

- Thin smear: Monolayer of RBCs, can speciate and quantify but poor sensitivity and takes alot of time

- >5% parasitemia --> P. falciparum!!

- P. falciparum can infect all RBC (>1 parasite/RBC), P. ovale/vivax can only infect reticulocytes

- Banana shaped gametocytes --> P. falciparum!!

- Vector Control: Indoor residual spraying, insecticide treated bednets, and area spraying of DDT

- Personal Control: Chemo-prophylaxis, mosquito repelleants, behavioral changes, and vaccines

- Treatment: Quinine, quinidine, chloroquine, malarone, doxycycline, primaquine, mefloquine, and CoArtem

- Some meds are only for treatment and some are only for prophylaxis

- Combination therapy: Reduces resistance and quick vs. slow killing

- Babesia microti --> Looks ALOT like malaria on smears!!

- Vector: Ixodes scapularis (Lyme and HMA carrier)

- Reservoir: Rodent and cattle --> Different strains

- Also transplacental and blood transfusion transmission

- Symptoms: Asymptomatic or mild fever, chills, malaise, anorexia, fatigue, headache, myalgias, N/V, adbominal pain, jaundice, etc

- Severe disease: Immunocompromised or patients who have had their spleens removed

- Incubation: 1-6 weeks but 6-9 weeks in transfusion transmissions

- Incidence: Highest in MA and New England

- Human/rodent cycle: Sporozoites introduced into host, becomes trophozoites, infects RBCs and becomes merozoite

- Merozoite becomes gamete in reservoir/rodent

- Tick cycle: Tick ingests gametes, fertilization occurs in gut, becomes ookinete, enters salivary gland, undergoes sporogony, sporozoites produced in salivary gland

- Lab findings: Anemia with hemolysis, thrombocytopenia, proteinuria, elevated ALT/AST, and increased bilirubin

- "Maltese Cross" on thick and thin smears

- IgG detection via indirect IF

- PCR

- Most important factor is the infecting species --> Is it P. falciparum or not??

- Immune and genetic status of the host affects severity

- Prevention of mosquito bites and chemoprophylaxis

- Treatment seeks to inhibit parasite multiplication and development

- Drugs: Chloroquine, mefloquine, atovaquone/proguanil, primaquine, and doxycycline

1. Blood schizonticidal agents --> Against blood stage parasites

2. Tissue schizonticidal agents --> Against liver stage parasites

3. Prophylaxis --> Prevent blood stream infection by inhibiting replication of liver-stage parasites

- 4-aminoquinolines (chloroquine)

- Quinoline-methanols (mefloquine)

- Hydroxynapthoquinone (atovaquone)

- Folate antagonists: DHFR inhibition (proguanil) and PABA competition (sulfonamides/sulfones)

- Doxycylcine: Protein synthesis inhibitor

- Artemisin derivatives (artemether, artesunate)

- 4-aminoquinoline

- Active against erythrocytic schizonts of P. malariae and ovale, most P.vivax, and P. falciparum

- Activity: Large ring forms and mature trophozoite stages

- Given orally, well absorbed, widely distrubted, and very long elimination

- Weekly dosing --> Great for prophylaxis

- Target: Process of Hb digestion in food vacuole

- Resistance: Interference with chloroquine accumulation and efflux mechanisms --> High for P. falciparum

- Adverse effects: headache, GI upset, pruritus, and visual problems with prolongued use (5 years)

- Can be used in pregnancy!!

- Artemether: Endoperoxide moiety

- Lumefantrine: Inhibits formation of beta-hematin

- Target: Nucleic acid and protein synthesis

- Use: Acute and uncomplicated P. falciparum infection

- Highly bound to serum proteins

- Artemisinin/artemether has short half-life (2 hours) and lumefantrine has 3-6 day half-life

- Not suitable for prophylaxis!!!

- Hydroxynapthoquinone

- Target: Electron transport

- Highly lipophilic --> 2-3 day half-life and poor CNS penetration

- Uses: Broad spectrum for antiprotozoal infections, P. falciparum and maybe P. vivax

- Resistance: Develops rapidly when used alone

- Usually used in combination with proguanil (Malarone)

- Folate antagonist --> Inhibits dihydrofolate reductase

- Poorly absorbed

- Short half-life

- Slow schizonticidal activity in erythrocytic forms

- Activity: Sporozoites and hepatic forms of P. falciparum

- Combination with atovaquone (Malarone) --> Daily dosing for prophylaxis and treatment

- Flourinated 4-quinoline methanol

- Activity: chloroquine-resistant P. falciparum

- Moderately well absorbed

- Extensively distributed

- Slowly eliminated --> Weekly dosing

- Highly bound to plasma proteins

- Hepatic clearance to inactive metabolites

- Target unclear

- Resistance: P. falciparum strains

- Uses: Prophylaxis and treatment of uncomplicated malaria

- Adverse Effects: GI disturbances, headache, insomnia, abnormal dreams, and neuropsychiatric events

- Contraindications: Psychiatric illness, cardiac arrhythmia and seizures

- May be used in pregnancy!!

- 8-aminoquinolone --> Tissue schizonticidal drug

- Activity: Exoerythrocytic forms of P. ovalen and vivax and gametocytes

- Target: Mitochondrial function

- Use: Treatment of relapsing P. vivax and ovale and prophylaxis

- Contraindications: G6PD deficiency --> Hemolysis!!

- Usually well tolerated

- Doxycycline: Protein synthesis inhibitor --> Not for patients <8 years

- Quinine and quinidine (Cinchona alkaloids): Parenteral (IV) administration for severe malaria --> Treatment only and significant toxicity

- Parenteral artesunate: Only available from the CDC for severe malaria

- GI luminal parasites

- Giardia lamblia, Entamoeba histolytica, Isospara belli, Cyclospora cayetanensis, Cryptosporidium parvum, and Trichomonas vaginalis

- Rarely invasive but E. histolytica can disseminate

- Therapy directed at the site of infection

- Nitroimidazoles --> Metronidazole and tinidazole

- Aminoglycosides --> Paromomycin

- Folate antagonist: Trimethoprim/Sulfamethoxazone

- Thiazolide --> Nitazoxanide

- Activity: Many protozoa

- Use: Bacterial infections, invasive amebiasis, giardiasis, and trichomoniasis

- Administration: IV and PO

- Metabolism: Hepatic

- Mechanism: Electron sink --> Damages DNA

- Side effects: GI distress, dysgeusia, and dizziness

- Adverse effect: Disulfiram-like effect with alcohol and potentiates warfarin

- May be used after first trimester of pregnancy

- Aminoglycoside

- Administration: orally --> Poor absorption

- Side effects: GI symptoms

- Can be ototoxic or nephorotoxic in renal failure patients

- Uses: Giardia, Cryptosporidium, and Entamoeba cysts

- Licensed in 2002 to treat Giardia and Cryptosporidium diarrhea

- Absorption: Well absorbed in GI

- Well tolerated but sometimes mild/transient GI symptoms

- Uses: Broad antiprotozoal and antihelminthic activity

1. GI and tissue nematodes (roundworms)

- Ascaris lumbricoides

- Enterobius vermicularis

- A.duodenale/ N. americanus

2. Trematodes (flukes)

- Schistosoma spp.

- Clonorchis/Opisthorchis

3. Cestodes (Flatworms)

- Taenia spp.

- Echinococcus spp.

- Agents listed for US use

- Benzimidazoles --> Albendazole and mebendazole

- Macrocyclic lactones --> Ivermectin

- Isoquinoline-pyrazine --> Praziquantel

- Albendazole (mebendazole no longer available in the US)

- Use: Broad spectrum for helminth infections

- Mechanism: Inhibition of microtubule polymerization, binds to B-tubulin

- Active against larvae, adult and egg stages

- Results in immobilization of parasite over days

- Not recommended during pregnancy

- Absorption: Variable but increased with fatty meal

- Metabolism: Rapid hepatic metabolism

- Distribution: Well distributed including into cysts

- Elimination: Renal excretion of metabolites

- Low toxicity --> GI upset

- Potent anti-helminthic activity

- Macrocyclic lactone

- Use: Nematodes and ectoparasites (strongyloides, onchocerciasis, and scabies)

- Mechanism: Binds chloride ion channels to hyperpolarize nerve cells and kill parasite

- Administration: PO, well absorbed and long half-life

- Toxicity: Low but may trigger allergic reaction

- Safe during pregnancy

- Isoquinoline-pyrazine

- Mechanism: Increases membrane permeability to cations --> Spastic paralysis with low and tegument damage with high doses

- Administration: Well absorbed orally

- Metabolism: Hepatic metabolism to inactive metabolites

- Interactions: Modified by P450 drugs (inducers or inhibitors)

- Toxicity: Low --> Safe during pregnancy

- Use: Schistosoma spp, tapeworm, and fluke infections

- 2 or more of the following criteria must be fulfilled:

1. Temperature >38C or <36C

2. Heart reate > 90 beats/minute

3. Respiratory rate > 20 or PaCO2 < 32mmHg

4. WBC >12K or <4K/mm3, or >10% bands

- Causes: Bacterial infections, non-infectious pancreatitis, major trauma, viral infections, and fungal infections

- SIRS due to an infection

- Septic shock --> Shock due to sepsis

- Severe sepsis --> Sepsis with failure of at least one organ system

- 750 million patient discharges --> 8.7% increase/year

- More commonly caused by G+ than G-

- Highest mortality among black men

- Little improvement in mortality since the advent of antibiotics --> 24% 28 day mortality and 33% 90 day mortality

- Due to dysfunctional inflammation and clotting systems

- Hematoma --> Hemorrhage within a space

- Bruises --> Petechiae, purpura and ecchymosis

- Petechiae --> Small clots all over the place under the skin

- Ecchymosis --> Bruise

- Clotted blood within the vascular space 

- Composed of cellular elements from the blood

- Includes platelets, RBCs, WBCs and proteins from coagulation cascade

- Arterial: Arises at site of injury --> Lines of Zahn (layers of RBCs and then platelets/fibrin)

- Venous: Arises at site of stasis --> Less firmly attached and usually in LE

1. Vasoconstriction

2. Primary hemostasis

3. Secondary hemostasis

4. Thrombosis and anti-thrombotic events

- Smooth muscle cells contract

- Blood and platelets are now exposed to underlying ECM

- Platelet adhesion to ECM via von Willebrand's Factor

- Granule release from platelets

- Platelets aggregate to form primary clot

- Endothelial cells begin to express tissue factor

- Tissue factor activates the clotting cascade

- Clotting cascade produces fibrin which binds to the primary plug

- Fibrin eventually completely replaces the primary plug of platelets and ECM

- After secondary plug forms, anti-thrombotic events begin

- Helps to allow tissue to be repaired and have resident tissue replace damaged tissue and clot

- Tissue plasminogen activator --> Cleaves fibrin

- Usually have anti-thrombotic properties

1. Anti-platelet activity --> Provides physical barrier from ECM and produce NO and prostacylcin PGI2 which inhibit platelets

2. Anti-coagulant activity --> Heparin-like molecules, thrombomodulin, and tissue factor pathway inhibitor

3. Fibrinolytic effects --> Tissue type plasminogen activator

1. Heparin-like molecules --> Binds anti-thrombin III and inactivates thrombin and coagulation factors

2. Plasmin --> Breaks down fibrin strands

3. Plasminogen Activator --> Activates plasmin

4. Thrombomodulin --> Binds thrombin --> Activates Protein C

5. Tissue Factor Pathway Inhibitor --> Inactivates factors VIIa and Xa

6. Protein C and S --> Inactivates Factor Va and VIIIa

1. von Willebrand Factor: Binds platelets to underlying ECM (collagen)

2. Tissue factor: Activates clotting cascade

3. Plasminogen Activator Inhibitors: Decreases fibrinolysis

4. Thrombin: cleaves fibrinogen to produce fibrin

1. Adhesion: With collagen and vWF

2. Secretion: Ca++ and ADP

3. Aggregation: ADP and Thromboxane A2

- Clopidogrel (drug) blocks ADP binding to receptors to prevent thrombus formation

- Each step requires co-factor and calcium

- Uses phospholipid complexes

- Factor II (prothrombin) is activated by factor Va + Xa on cell phospholipid membrane

- Factor IIa (thrombin)

- Cleaves Factor I (fibrinogen) to Factor Ia (fibrin)

- Natural Anticoagulants: Anti-thrombins, Protein C, Protein S, and Tissue Factor Pathway Inhibitor

- Plasminogen: Inactive plasmin precursor

- Plasmin: Interferes with fibrin polymerization and breaks down fibrin

- Plasminogen activators: Turn plasminogen into plasmin

- Dysfunctional coagulation in sepsis

- Can lead to disseminated intravascular coagulation (DIC) --> Blood clots where it's not supposed to and doesn't where it should

- Activated Protein C (aPC) was approved for sepsis treatment --> Withdrawn Oct 2011 because it was ineffective

- Endothelial cell injury --> Complete or partial

- Abnormal blood flow --> Turbulent or sluggish

- Hypercoaguable state --> Genetic or acquired

- Propagate: Continue to grow, may eventually occlude

- Embolize: Break free and travel

- Dissolution: Lyse and degrade due to fibrinolysis

- Organize and recanalize: Granulation tissue shrinks the thrombus and new vascular channels form

- Pulmonary thromboemboli: Comes from deep veins in the pelvis or legs --> Can occlude large vessels

- Fat emboli: After long bone fractures --> Can occlude

- Air emboli: Decompression sickness

- Amniotic fluid emboli

- Septic emboli: Occlusion due to fragments of necrotic tissue

- Ischemic necrosis occurs due to loss of blood flow to an area of tissue

- Tissue generally appears wedge shaped

- Hemorrhagic --> In areas with dual blood supply or in areas that have been reperfused after occlusion of a vessel --> Appears bright red

- White/anemic --> Occlusion of an end arteriole

- Increased levels of TNF, IL-6 and IL-8

- Specific inhibitor therapy thought to improve survival --> Actually doesn't!!

- Cytokines may be markers rather than actual mediators of disease

- Lymphocytes: Accelerated apoptosis in several organs and blood

- Neutrophils: Decreased apoptosis so that they persist longer in the circulation --> Increased WBC count