MicROBIOLOGY UNIT EXAM 3 Pt. 2 Flashcards

Question

Pharmacokinetics of Tetracycline Bioavailability range, route, avoid, binds to tissues undergoing ____, penetrates _____ well,

Answer 1

•Orally active: range from 30% bioavailability for chlortetracycline to 95% for doxycycline. - Dairy products, Mg++, Ca++and Al+++ions chelate tetracyclines and produce a non-absorbable complex * Bound to tissues undergoing calcification (teeth and bones * Penetrate tissues well –high concentrations in liver and kidney * Cross the placenta * Minocycline has high concentration in tears & saliva and can be used to treat meningococcal carrier state (not active) Note: Effect of milk on tetracycline absorption is more inhibitory than Al(OH3) "antacid"

Answer 2

* Metabolized to varying extents, especially glucuronide formation which is very polar and ends up in kidney and biliary excretion. * All undergo enterohepatic circulation except for doxycycline glucuronide * Renal excretion is important for all except doxycycline which is excreted in the feces

Answer 3

* Irritation of gastric mucosa –GI distress * Deposition in bone and primary dentition (permanent teeth) during calcification (contraindicated in children sunburn * Vestibular disturbance with minocycline * Azotemia, Fanconi-like syndrome with outdated preparations

Answer 4

* Antacids * Increased digoxin toxicity in 10% of patients * Increased warfarin activity due in part to decreased intestinal flora which produce vitamin K Note: TETRACYCLINE limits the growth of normal flora (organisms) that normally metabolize digoxin. Thus need to change the dose of digoxin e.g. decrease the dose b/c more digoxin will be absorbed than normally.

Answer 5

- greater risk of toxicities with nitro group on a benzene ring. 1. Antibacterial action: Binds to 50s to a site very similar to to macrolides and clindamycin- interfering with both peptidyl transferase (make peptide bond) and translocation. 2. Resistance: –Enzymatic conversion to an inactive product by bacteria (acetyl CoA transferase) –Decreased affinity ``` 3. Spectrum –H. influenzae –Acute typhoid fever –Rickettsial infections (Rocky Mountain Spotted fever) –Anaerobic infections ```

Answer 6

Chloramphenicol Pharmacokinetics: * Orally active; parenteral preparations also * Well distributed; even enters CNS in absence of inflammation * Crosses placenta * Extensive metabolism by host. Ultimate product is a glucuronide * Excreted in urine Chloramphenicol Blood Levels in Two Different Age-groups of Children: 3-5 days old vs 1-5 year olds: Older children have a much higher rate of excretion.

Answer 7

A glucuronide, also known as glucuronoside, is any substance produced by linking glucuronic acid to another substance via a glycosidic bond. This links back to the competition aspect of HbF bursting and heme is now competing to get glucuronosylated.

Answer 8

•Hematological –Hemolytic anemia in G-6-P DH deficiency –Reversible anemia, leukopenia and thrombocytopenia –dose related; occurs during therapy –Idiosyncratic (dependent on the number of COURSES of CHLORAMPHENICOL Rx Treatments!!!) aplastic anemia –probably allergic in origin •Gray baby syndrome - at high enough doses will affect host mitochondria of these growing infants and thus cannot use oxygen ---> gray color. Fail to thrive. Adjust dose to weight as opposed to surface area. •Drug interactions because of CYP 450 inhibition: caution in patients on warfarin, phenytoin, etc. Note of caution: Easier to reverse adverse effects of penicilin compared to chloramphenicol --> aplastic anemia. Thus more cautious when administer this Rx.

Answer 9

* Anaerobic infections due to Bacteroides fragilis * Typhoid fever and H. influenzaemeningitis when first line therapy fails or cannot be employed * Pneumococcal or meningococcal meningitis in penicillin-allergic patients * Rickettsial diseases as a substitute for tetracycline( Sensitivity, ESRD, pregnancy, particularly children

Answer 10

Rx is effective against Gram negative aerobes and are bacteriocidal. * Binding to 30s subunit prevents initiation of protein synthesis * Blocks further translation & causes premature termination * Causes misreading of mRNA codon by binding to the 3rd codon. * Entry across bacterial cell membrane occurs via an active transport system that REQUIRES OXYGEN because Rx is polar. Note: Aminglycosides are bacteriocidal as opposed to most of the protein synthesis inhibitors that are bacteriostatic.

Answer 11

* Absence of the oxygen-dependent transport system (ACTIVE TRANSPORT TO GET AMINOGLYCOSIDE INSIDE) –obligatory anaerobes are resistant * Decreased affinity at the 30s subunit binding site * Plasmid associated inactivating enzymes that can acetylate, adenylate or phosphorylate the aminoglycoside

Answer 12

``` AC = acetylation AD = adenylation P = phosphorylation Bar = bacterial plasmid enzymes will be likely to alter the fxnal group and render it ineffective. ``` Natural Resistance! Amikacin - Most of the fxnal groups are resistant to the modification by the bacterial plasmid enzymes as opposed to Kanamycin- more sensitive to modification. Amikacin due to the resistance of being modified by plasmid enzymes DOES NOT lend itself to cross resistance by all members of the bacterial class. CROSS RESISTANCE DOES NOT OCCUR! E.g. gave a pt Kanamycin and they became resistant during Tx. The bacteria will not have a cross resistance to Amikacin thus it will be effective.

Answer 13

•Streptomycin –Mycobacterium tuberculosis •Gentamicin, tobramycin, amikacin –Gram negative aerobic bacteria Pseudomonas aeruginosa •NOTE: aminoglycosides are frequently combined with ß-lactams to treat serious, life-threatening infections because of synergy between the groups.

Answer 14

Tularemia Infections due to Enterococci Infections due to Pseudomonas Aeruginosa

Answer 15

* Must be given parenterally * Once a day dosing because exhibit dose-dependent killing •Distribution -extracellular fluid; do not enter CSF - Dissolve well but don't cross membranes well. Are highly polar * Cross the placenta * Concentrated in renal cortex and endolymph (vestibular and cochlear apparatus.) * Dependent on glomerular filtration (as opposed to beta-lactams which are also actively secreted into kidney tubules) for elimination * Therapeutic monitoring (because have a narrow therapeutic range thus have to routinely monitored esp. when getting infusion over a week or so.)

Answer 16

3 times a day because of the dependency of glomerular filtration rate. Once a day give the same of cumulative dose with the 3 times a day. We get 50 % of the time (12 hrs) exposed to concentrations of adverse effects. With 3 times a day (18 hrs) exposed to concentration of adverse effects. Killing of bacteria - dose dependent (more the dose the more the killing) Adverse effects - longer the time exposed to drug the increase in severity of adverse effects. Note: concentrations of adverse effects are above the threshold - - - -. No sig difference between the adverse effects of once a day vs 3 times a day and clinical difference not really apparent. Cheaper and less likely to miss a dose with once a day administration.

Answer 17

Patient factors affecting dosing of aminoglycosides * Age - increase in age proportional to decrease of GFR. Starting at age 50 every decade decrease of about 15% GFR * Obesity - Not as much fluid in higher fat content thus will end up with higher [ ] in extracellular fluid * Renal function - This goes for any antibiotic.... best way is to change length of time between time if there is impaired GFR. * Pregnancy * Hepatic function- this factor does not have a significant role for amino glycoside administration - If there is muscle wasting (as in the elderly) you have normal creatinine levels but decreased GFR

Answer 18

* Ototoxicity - Either vestibular or cochlear function. Cause loss of hearing or be dizzy. * Fetal auditory toxicity - reason why it is not given during pregnancy. * Nephrotoxicity * Neuromuscular paralysis

Answer 19

Encounter Entry Spread - Agent spreads from site of entry; this step doesn't always have to occur. Can remain localized. Multiplication/Colonization Damage - Agent or host response causes damage Outcome - Agent wins, host wins, coexistence Note: Defenses at each step!!!

Answer 20

Prebirth - uterine environment normally sterile, but congenital infections possible (transplacental) - E.g. rubella, syphilis, HIV, cytomegalovirus Birth - microorganisms in vaginal canal (mother’s antibodies sometimes protect); skin contact Types of Encounter: - Exogenous- some pathogens never establish normal flora agents in the environment - food, insect bites, etc. exchange of bodily fluids - sneezing, sex - Endogenous agents in or on the body normal flora in the wrong place Colonization- implies that the patient has a sufficiently high concentration of organisms at a site that they can be detected, yet the organism is causing no signs or symptoms. A carrier is a person who is colonized with an organism and may transmit the organism to other people. Colonization can persist for days to years, with resolution influenced by the immune response to the organism, competition at the site from other organisms and, sometimes, use of antimicrobials.

Answer 21

``` Without crossing epithelial barriers • Inhalation via aerosol droplets, dust • Ingestion of food or water • No entry or penetration into tissues - toxins (cholera, whooping cough, cystitis) ``` Crossing epithelial barriers • Pass through epithelia directly - bind to receptors • Insect bite or break in skin • Burrowing worms Organ transplants • Kidney transplants (CMV) Blood transfusions • HIV, Hepatitis B Virus Note: with infants and children a normal floral lacks thus a colonization that normally would not be an infection to adults may be so along with the toxification.

Answer 22

Spread - Lateral propagation (to contiguous tissues)- may be done so by enzymes that can break down muscle, tissue and lead to dissemination - Dissemination to distant sites - Microbial motility- e.g. vibrio cholera, bacteria in liquid areas. ``` **Enzyme action • hydrolases, elastases • collagenases, proteases • hyaluronidases, DNases • keratinases ``` Multiplication Depends on environment Incubation period - Early defenses, Growth Nutrition Antimicrobial substances Iron limitation Temperature optimum pH - Stomach acid Population density - quorum sensing: colony will get a sense of their density and with the favorable conditions decide how much more to grow. can occur within a single bacterial species as well as between disparate species, and can regulate a host of different processes, essentially serving as a simple communication network. Adherence

Answer 23

Mechanical obstruction- rare for bacteria, more common for parasites to do this. E.g the parasite that cause elephantiasis. Hookworms or helminths are large enough to block normal function Cell death - cytolytic toxins, activation of cell-killing WBCs Toxins botulinum, tetanus Inflammation and immunoprotective mechanisms Ag-Ab complexes (glomerulonephritis) Cell-mediated immunity-activation of macrophages (TB)

Answer 24

Depends on complicated interplay between human host and microbe Agent wins and host dies Host wins and disease is cleared Coexistence as with the normal flora

Answer 25

Opsonization of bacteria engulfment by PMN/macrophage phagosome fuses with lysosomes ==> phagolysosome Exocytosis of bacterial fragments

Answer 26

1. Capsule: Streptococcus pneumonia 2. Important Surface Components: protein A performs an extremely tight interaction to IgG thus blocks the Fc portion and now not available for Fc receptor to bind. - Staphylococcus aureus: protein A binds Fc portion of IgG molecules; prevents opsonization - Streptococcus pyogenes: M protein protects from phagocytosis 3. Killing Phagocytes Bacterial enzymes that lyse phagocytes Streptococcus pyogenes---> Streptolysin Clostridium perfringens ---> Alpha-toxin

Answer 27

1. Escape the phagosome before fusion of lysosome ``` Rickettsia Trypanosoma Shigella Listeria Francisella ``` 2. Tolerance of being inside phagolysosome- a. Catalase, superoxide dismutase detoxify oxygen intermediates b. Some cell walls are refractory to destruction by lysosomal proteases ``` Coxiella Ehrlichia Leishmania Mycobacterium leprae Salmonella typhi ``` 3. Avoidance can remain in phagosome for a period of time. Can block the fusion with lysosome and may continue to divide although slowly. Chlamydia Mycobacterium tb Legionella Brucella Toxoplasma

Answer 28

Intracellular Growth- permits bacteria to use the cell as a place to grow and hide from the immune responses. Intracellular replication gives cells a place to grow and protects from antibodies of the immune system. ``` Mycobacterium sp. Rickettsiae Francisellae Brucellae Chlamydiae Listeria monocytogenes Salmonella typhi Shigella dysenteriae Yersinia pestis Legionella pneumophila ```

Answer 29

Immune response must elicit new attack upon antigenic variation. E.g when the bacteria count is low as a result of an effective immune response the bacteria can undergo antigenic variation Neisseria gonorrheae pilin protein Trypanosoma surface glycoproteins Borrelia (Lyme disease), Neisseria (gonorrhea), Plasmodia (malaria)Polysaccharide capsule buries C3b component of complement and prevents opsonization

Answer 30

``` Capsules/slime layers Pili/Adhesins Biofilm formation Invasins Type III secretion systems sIgA proteases Fe binding proteins Toxins ```

Answer 31

Capsules: Most common bacterial mechanism to avoid phagocytosis * Prevent phagocytosis – prevent binding of opsonins to bacteria AND interaction between opsonins and their phagocyte receptors on Adhesion of phagocytes and binding of opsonins * Complement-mediated bacterial cell lysis * Enhance adhesion to the host cell * Prevent bacterial desiccation - e.g. coughing up a bacterium onto a surface it may survive longer.

Answer 32

Adhesins: - Protein or carbohydrate molecules bind tightly to sugars on target tissue - Prevent washing away - bladder, intestine, blood vessels 1. Pili 2. Afimbrial adhesins- Afimbrial adhesins refer to proteins that serve as adherence factors, but do not form the long, polymeric fimbrial structure. Afimbrial adhesins generally mediate more intimate contact with the host cell that occurs over a shorter range than with fimbriae. 3. Techoic acids from the gram positive bacteria

Answer 33

Bacterial adaptation that facilitates colonization •a sticky web of polysaccharides (slime) anchors cells e.g. dental plaque, indwelling catheters, valves •protects from host defenses and antibiotics

Answer 34

Invasins - Proteins that help bacteria cross mucosal membranes Shigella, Salmonella, Yersinia - invasin protein allows binding of bacteria to M cells of colon and encourage uptake, or go from one cell to another Genes for invasion machinery encoded on a Pathogenicity Island PAI - very large, unstable chromosomal regions Sets of genes encoding numerous virulence factors - Regulated by a single stimulus Mobile genetic element transferrable as a unit to other bacteria (TGEs)

Answer 35

Type III Secretion Systems- more effective to get enzymes/toxins directly into a host cell via connection than just secreting enzymes/toxins extracellularly. Export system - delivers proteins through both inner and outer membranes of Gram negative pathogens

Answer 36

Mucin: proteoglycan mucin protects mucosal cells, contains secretory IgA Host defense - sIgA binds to glycoprotein in mucin layer and traps bacteria; prevents bacteria from reaching mucosa Bacterial offense - sIgA protease -cleaves hinge region (much more likely to cause bacterial infection in mucosal regions) of sIgA, releasing bacteria

Answer 37

Iron is critical for humans and most pathogens - required for cytochromes, cofactor for enzymes, etc * Iron limitation restricts bacterial growth * Low free [Fe] in humans ***To compete with lactoferrin/transferrin for iron, bacteria contain Siderophores- Fe chelators

Answer 38

Toxins are bacterial products that directly harm tissue or trigger destructive biologic activities Cell envelope components: Endotoxin, teichoic acid, etc. Alarm signals to immune system --> release acute phase cytokines, fever, vasodilation, shock! Exotoxins: cytolytic enzymes/hemolysins or receptor binding proteins - Damage cell membranes (phospholipases or lecithinases) - Pore forming proteins - Targets: ribosomes, transport mechanisms, intracellular signaling Note : Exotoxins are more limited to certain species or even only certain subspecies (strains)

Answer 39

Corynebacterium diphtheria- non invasive, toxin does the damage. - Single virulence factor: Diphtheria toxin Staphylococcus aureus - Many virulence factors: adhesins, degradative enzymes, toxins, catalase, coagulase Escherichia coli - Different strains of one species have different virulence factors: urinary tract infections v. diarrhea v. meningitis

Answer 40

Cooperation between microorganisms and humans is the rule, disease is the exception. The majority of these relationships are symbiotic (mutual benefit) Commensal (co-existence, no harm). 1) the virulence of the microorganism 2) the response of the host.

Answer 41

Infectious disease occurs when there is tissue injury (leading to inflammation) or altered host physiology.

Answer 42

Acute inflammation: redness, swelling, increase of temperature 1. Polymorphonuclear leukocytes (aka PMNs, neutrophils) (e.g., acute pneumococcal or Klebsiella pneumonitis, acute bacterial colitis, acute staphylococcal osteomyelitis, Acute laryngotracheitis). a. Pyogenic (suppuration) when there is significant necrosis ---> abscesses (pyogenic cocci, some gram (-) bacilli)  ---------------> furuncles (Staph.) or ----> cellulitis (Strep.) or necrotizing pneumonia b. Adhesins, fimbriae, bacterial peptides/proteins, lipopolysaccharides (LPS), cytokines, C5a. 2. Exceptions: clinically acute disease (e.g.Typhoid fever, S. typhosa) but with a mononuclear cell response associated with reactive hyperplasia of the intestinal and systemic lymphoid cell population; Bordetella pertussis.

Answer 43

Chronic- lymphocytes, neutrophiles, monocytes 1. Tuberculosis: necrotizing (caseating) granulomata 2. Brucellosis and tuberculoid type Leprosy: non-necrotizing granulomata 3. Plasma cell infiltrates and granulomata: Treponema pallidum (syphilis) 4. Chronic, non-granulomatous but with aggregation of macrophages: Mycobacterium avium intracellulare (MAC), lepromatoid Leprosy. C. As a generality, intracellular bacteria induce chronic inflammatory (immune) reactions. Note: Mixed acute and chronic inflammation can exist, and Cytologic changes +/- inflammation (viruses are responsible for this one)

Answer 44

mainly Gram + cocci that evoke a neutrophilic exudation and account for most of the suppurative lesions in medical practice including: 1. Staphylococcus aureus- furuncle/carbuncle, bronchopneumonia, impetigo, osteomyelitis, toxic shock 2. Streptococcus pyogenes and pneumoniae: pharyngitis,URTI, lobar and bronchopneumonia; scarlet fever, cellulitis, necrotizing fasciitis, glomerulonephritis, rheumatic fever 3. Neisseria (Gram -) -meningitis, gonorrhea, arthritis

Answer 45

mainly Gram-negative bacilli 1. E.coli (UTI, Hemolytic-Uremic Syndrome, severe colitis/peritonitis), pyelonephritis. 2. Klebsiella pneumoniae (bronchopneumonia with abscess and pleural involvement) 3. Pseudomonas aeruginosa (burns): bronchopneumonia.

Answer 46

1. Hemophilus influenzae type B: encapsulated, particularly young children affected, (meningitis, bronchiolitis, epiglottis) 2. Bordetella pertussis (whooping cough) 3. Cornyebacterium diphtheriae: (exotoxin  local necrosis- e.g. laryngeal pseudomembrane formation - and systemic effects - e.g. myocardial necrosis)

Answer 47

Enteropathogenic bacteria- cause GI disturbances by toxins (Vibrio cholerae, Clostridium difficile, E.coli O157:H7), invasion (Salmonella typhi), or both (dysentery-Shigella sp.)

Answer 48

Gram pos rods (toxin producers) 1. Clostridium tetani and C. perfringens (spore contamination of wounds --->  toxin) 2. C. botulinum (ingest preformed toxin), Septic clostridial infection. Cause rapid and severe tissue damage, sometimes without inflammation, that frequently ---> death.

Answer 49

1. Treponema pallidum: Syphilis: primary (chancre most commonly on either penis or vulva), secondary (rash, condyloma lata), tertiary (gumma, CNS, CV, congenital). Plasma cells are characteristic and distinctive inflammatory cell reaction. Occasionally also granulomas in secondary and tertiary stages. 2. Borrelia burgdorferi-Lyme Disease-primary, secondary, tertiary. Chronic inflammatory reactions, may lead to fibrosis and tissue destruction.

Answer 50

1. Intracellular bacteria 2. More common than Neisseria as a sexually transmitted disease organism causing cervicitis, pelvic inflammatory disease, urethritis, epididymitis. In impoverished countries a leading cause of blindness (trachoma). Chronic inflammatory reactions, sometimes with immunoblast clusters. C. psittaci: pneumonia. 3. More recently are being implicated in pathogenesis of atherosclerosis! (persistent low grade intravascular infections  mild inflammation fibrosis)

Answer 51

1. Intracellular bacteria 2. Cause chronic inflammatory reactions 3. Some rickettsia are associated with vasculitis due to injury to endothelial cells.

Answer 52

1. Free-living bacteria | 2. Cause inflammatory reactions

Answer 53

Tx: adhesin molecules against the surface molecules of bacteria that interact with host surface.

Answer 54

area of millions of neutrophils and liquefied tissue debris. The lysosome connects and secretes into not completely closed phagosome. Now all these enzymes get into host tissues ---> abscess.

Answer 55

Pseudomonas infection which leads to pus (BLUE/GREEN). This leaves behind a cavity from the suppurative inflammation.

Answer 56

Pus has destroyed the wall of the bronchiole and thus the acute inflammatory because to spread to peribronchial tissue. Septicemic abscesses in kidney break down tissue, disseminate --> metastatic abscesses. - multiple foci of infection in an organ is indicative of septicemia

Answer 57

Bacteria disseminate and leads to acute cardiac insufficiency where pus formed in the valve and left a huge gaping hole.

Answer 58

Seeing a spreading inflammatory process will see diffuse swelling "Cellulitis" ---> most likely Streptococcal

Answer 59

Bordetella pneumonia (mononuclear and interstitial) : intracellular in nature ---> chronic inflammatory Mononuclear cells respond to the intracellular bacteria.

Answer 60

A necrotizing granuloma with giant cells. Survive phagocyte, outlive phagocyte, induction of CMI. CMI doesn't kill TB thus becomes granuloma. Ghon complex (Primary Tuberculosis)

Answer 61

Occurs in upper apical lobe.

Answer 62

Informational

Answer 63

Brucella hepatitis (non-necrotizing granulomas)

Answer 64

Plasmacellular inflammation (Syphilis)

Answer 65

Staphylococcal infections - usually caused by the ingestion of the toxin present in the food

Answer 66

Three basic types: 1.A-B Type (A is enzymatic, B is binding) - B brings the A subunit to the cell. •Simple (A & B subunits, connected by S-S) •Complex (A & 5B subunits) 2.Membrane disrupting •Passive channel - membrane complex protein that may erupt holes into the membrane. •Phospholipase - cleaves the phosphate head groups off the outer leaflet of the membrane 3. Superantigens (mimic MHC ClassII/CD4+TH interaction) - much more likely to produce the various cytokines.

Answer 67

Bacterium adheres to mucosal surface. Bacterium synthesizes toxinogen. Cleavage --> active toxin. AB subunits held together by disulfide bonds. Toxin moves to target cell. B binds to cell surface receptor. Subunit A enters by: 1. Endocytosis, or 2. Translocation. Inside subunit A catalyzes enzymatic activity and exert toxic effects. Note: bacterium does not get into cell, the toxin produced is what transverses the cell and get into blood. In most cases the bacterium does not even cross the epithelial layer.

Answer 68

1. Some (not all) have NADase activity 2. NADase effects: a. stimulate adenylate cyclase (Increase cAMP) b. inactivate elongation factor 2 (block translation) ADP ribosylation Note: NADase an enzyme that catalyes hydrolysis of NAD+ to nicotinamide and adenosine diphosphoribose.

Answer 69

The exotoxin creates a non selective pore. H20 rushes in and cell swell and lysis The exotoxin is a phospholipase cleaving the phospho groups of the outer leaflet ----> unstable membrane

Answer 70

Antigen presenting cell with antigen stimulates T cells receptors 1 in 10^4 resulting in IL-2, T cell proliferation, T- B interaction, B cell proliferation, and Antibody production Superantigens: - Many (1 in 5) T-cells stimulated! - Excess IL-1, IL-2, IL-6, TNF-a, IFN-g ---> SHOCK!

Answer 71

Not common because of vaccine. K+ Tellurite selection- Potassium tellurite (K2TeO3) is used together with agar as part of a selective medium for growth of some bacteria (Clauberg medium). Corynebacteria and some other species reduce TeO32− to elemental Te, which stains the bacteria black. (SMALL, BLACK COLONIES) 1. Gm pos, clubbed ends, pleomorphic bacillus 2. Aerobic 3. Colonizes throat & nasopharynx, non invasive, thick, grey mucoid coat (pseudomembrane) that leaves bloody patches when removed 4. Clinical effects - heart and peripheral nerves Note : pseudomembrane formation particularly in the young covers the throat ----> suffocation (Death)

Answer 72

1. Iron regulated (low iron = high tox expression); DtxR repressor 2. Binds to heparin-binding EGF precursor (most cells of body) 3. ADP-ribosylates Elongation Factor-2 (EF2) 4. Simple A-B Note: Toxin is phage encoded; transcription is repressed by iron + DtxR repressor

Answer 73

1. Antitoxin & antibiotics (Penicillin or erythromycin) 2. "D" of DPT vaccine (toxin) 2004 - 5,000 deaths worldwide, largely due to incomplete vaccination

Answer 74

1. Small, Gm negative coccobacillus 2. Fastidious, slow growing 3. Colonizes region between airway and lungs 4. Disease: - cold symptoms, with paroxysmal coughing interrupted by whooping - extremely contagious, significant cause of morbidity worldwide (39,000,000 cases & 300,000 deaths!) - low incidence in USA (vaccination – P of DPT) - no known other carrier. Thus it is possible to eradicate. Vaccine is against the protein extract of pertussis. Long term death due to pneumonia. It can be invasive --> becomes intracellular (e.g. in macrophages) Note: may produce a fever but difficult to differentiate from a cold.

Answer 75

Virulence factors 1. Adhesins: attach to ciliated cells (esp. FHA = filamentous hemagglutinin) 2. Adenylate cyclase toxin: bacterial AC (which has no host intracellular regulation) translocates to cytoplasm of mammalian cell and increases intracellular cAMP. 3. Pertussis toxin: complex A/B toxin, stimulates host AC by inhibiting Gi via ADP ribosylation thus Gs is left unbalanced and increasing intracellular cAMP production Note: the high increase of cAMP is ultimately the cause of death --> e.g. leading to fluid in alveolar space (pneumonia)

Answer 76

Treatment 1. Antibiotics – (changes course only if early, but blocks spread) 2. Adequate oxygen support Prevention 1. Vaccine – P of DPT Note : Bordetella pertussis is a disease more likely to result in death in children 5 yo or less.

Answer 77

1. Gm neg rod; found in soil, water, animals 2. Colonies fruity odor and blue-green pigment 3. Minimal nutritional requirements 4. Obligate aerobe Pathogenesis: 1. Opportunistic infections (esp. immunocompromised and patients with catheters) 2. Both localized (e.g. pneumonia) and systemic (e.g. gets into circulation --> sepsis) infections 3. Infects lungs of CF patients, cancer, burns/wounds and catheter sites, ear (otitis externa – swimmer’s ear), eye (contact lenses are risk factor), pneumonia, endocarditis (esp. drug users) Note : doesn't require much thus we are exposed to it all the time but does not have very good virulence effectivness.

Answer 78

1. Alginate – thick gel, slime layer (antiphagocytic) 2. Pili – required for initial colonization (replaced by mucoid slime layer)

Answer 79

Aggressive use of 2 antibiotics because: - resistance mechanisms - opportunistic infection Prevention Strict attention to control measures Note: aggressive use because it's a soil bacteria and will have resistance mechanisms. Especially in the case of immunocompromised patients. drug resistance common and P. aeruginosa is opportunistic

Answer 80

Gm positive, obligate anaerobes Spore forming Three major clinical species: 1. Clostridium tetani - tetanus 2. Clostridium botulinum - botulism 3. Clostridium perfringens - gas gangrene 4. Clostridium difficile -obligate anaerobes but as spores can survive to exposure of oxygen. with favorable conditions will begin to grow vegitatively.

Answer 81

Clostridium tetani A. Gm + slender rods, terminal spores B. Feces and contaminated soil (high density) C. Infectious form - spore in anaerobic environment D. Tetanus - spastic paralysis - localized (lock jaw) E. 50 – 70 deaths/yr in USA, almost 1 million worldwide F. Diagnosis – clinical (infection is often minor). Vaccinate against toxin. Little toxin is lethal! Note: often introduced as a polymicrobial solution. Very little growth of bacteria because the toxin is so toxic. Vaccination is against the toxin

Answer 82

Toxin: 1. Simple A-B type toxin 2. A subunit – endopeptidase, blocks release of inhibitory neurotransmitters - Results in the continuous stimulation → spastic paralysis tetanus toxin go up motor neuron and passes transsynaptically to the inhibitory synapse. If we block the inhibitory synapse thus we can't release the vesicles to inhibit the excitatory synapse vesicles.

Answer 83

Treatment: 1. Isolation (decrease stimulii) 2. Anti-tetanus Ig 3. Debride wound & antibiotic Prevention: T of DPT (inactive toxin) - inactive toxin every 10 years - previous exposure not protective because little infection

Answer 84

A.botulus - “sausage” disease- the bacteria would grow in sausages and thus consumption would lead to infection. B.40-80 cases/yr C.Three types of botulism: i. classic (food borne) – intoxication (the toxin is what gets ingested. No bacterial growth, no bacteria to treat.) ii. wound – bacterial growth (rare). Spores in wound, bacteria grow, toxins produced iii. infant – bacterial growth (HONEY!). Spores ingested, bacteria grow in GI, toxin produced D.Simple A-B type toxin, cleaved in GI E.flaccid paralysis: Initial slurred speech, difficulty swallowing, visual disturbance, progressive flaccid paralysis results in respiratory paralysis or cardiac arrest Note: Honey can be home to the C. botulinum spores. Spores that are ingested exist in the intestine. Spores in the GI would not do well and eventually will be done away. Infants don't have normal flora thus we don't give honey because the spores can be in the honey.

Answer 85

Affect peripheral cholinergic synapses (NOT CNS), block release of acetylcholine and cause FLACCID paralysis Botulinum toxin, subunit B binds to the gangliosides of motor end plate. Subunit A blocks the release of ACh at the motor end plate ---> lack of excitation leads to flaccid paralysis works on the motor neuron. Blocks the release of vesicles containing acetylcholine

Answer 86

Symptoms reflect where toxin acts, which is thought to reflect action of B SUBUNIT!

Answer 87

Treatment: 1. Anti-botulinum Ig (it is an intoxication) 2. Antibiotic for infant and wound botulism Prevention: Proper food handling

Answer 88

A.Gram positive, stout, truncated, spores B.Obligate anaerobe C.Vertebrate GI, spores in soil D.Pathogenicity - gas gangrene (myonecrosis) - food poisoning (7% USA) - self limiting ``` E. Virulence: - alpha Toxin (phospholipase) - enterotoxin - degradative enzymes (proteinases, DNAses, hyluronidase, collagenase) ``` Note: In GI can grow not well but if grows enough can make enough enterotoxin to be virulent.

Answer 89

Alpha-toxin - Lecithinase C (phospholipase) - Membrane disruption Gas gangrene - spores into severe, open wound with other bacteria - germinate & grow rapidly in anaerobic condition - rapid spread and necrosis, gas (CO2 & H2) formed from fermentation of tissue carbohydrates, copious pus, foul smell - uniformly fatal without intervention

Answer 90

Diagnosis - clinical grounds - disproportionate local pain; tachycardia; tachypnea; fever; delirium; skin becomes stretched, necrotic, blisters and then malodorous discharge (similar to nectrotizing fasciitis) Treatment - surgical debridement (from 100% to 30%) - penicillin IV (another 5%) - hyperbaric oxygen

Answer 91

Staphylococci - Gram + cocci - clusters - Nasopharynx, skin, GI Streptococci - Gram + cocci - pairs/chains - Nasopharynx, skin, GI

Answer 92

CATALASE TEST Staphylococci; YES catalase Streptococci; NO catalase

Answer 93

``` • Gm + cocci • Grow in high salt (7.5% NaCl) • Standard growth medium • Normal Flora • Resistant to drying/heat, many antibiotics  MAJOR problem in hospitals (spread by nasal & skin carriage) ``` Note: doesn't mean they like salt, and the drying and heat resistance not to the extent of spores.

Answer 94

1. Staphylococcus aureus (most common) - skin infections, osteomyelitis, toxic shock syndrome, food poisoning, large number types of infections. Including unrelated diseases due to the toxin carried in the bloodstream. 2. Staphylococcus epidermis - septicemia and endocarditis (implanted device). can colonize catheters & indwelling shunts. 3. Staphylococcus saprophytic - urinary tract infections, urinary tract infections. Can colonize catheters and shunts.

Answer 95

Coagulase Staphylococcus aureus + (causes clotting) Staphylococcus epidermidis - Staphylococcus saprophytic - fibrinogen --- coagulase binds to prothrombin ---> fibrin (clot)

Answer 96

Properties • Pathogenic strains often b-hemolytic, yellow pigmented colonies • Pathogenic capacity = surface molecules, extracellular factors + toxins blood agar plate- bacteria are lysing the blood cells and we get a zone of clearing - beta-hemolysis. There are lysing that exists with other blood cells but we use this for diagnostic purposes. Note: it has not been possible to develop a serologic assay.

Answer 97

• Fibronectin binding protein - adhesion • Clumping factor – binds fibrinogen (aggregates Staph) – prevent phagocytosis • Protein A (only S. aureus) – linked to peptidoglycan – bind Fc of IgG1, IgG2, IgG4 --> no phagocytosis since phagocyte Fc receptor can't bind – prevent phagocytosis

Answer 98

1. Catalase – counteract PMN’s 2. Coagulase – clotting (poor penetration by WBC’s) 3. Hemolysins - a (“a toxin”): transmembrane channels; cytolytic exotoxins attack mammalian cell membranes ---> hemolysis. transmembrane channel, dermatonecrosis, and lethality; 3 other hemolysins - may be cytotoxic for a variety of cells 4. b-lactamase – narrow spectrum (90% of strains) 5. Leukocidin – K+ channel, products capable of killing granulocytes and macrophages Note: With clotting have to debri the wound because the coagulse can form a "boil" and prevent WBCs from getting to the site

Answer 99

Exotoxins: Staph exotoxins - Exfoliative toxins – Scalded skin syndrome – desmosomal protease: cleaves the proteins the hold parts of the epithelial layer together. In this manner the toxin can be spread throughout the body with the need for bacterial penetration. Toxic shock syndrome – superantigen (exotoxin) – 20% S. aureus Enterotoxins( no infection. The effect is the toxin being ingested) – Food poisoning – superantigen (heating of food does not help. Have to make sure it is not present before ingestion. Unlike C. Botullium can be killed by heating food.

Answer 100

``` Skin & soft tissue Musculoskeletal Endocarditis Genitourinary Toxin based ```

Answer 101

Skin infections: - Folicullitis- infection starts at break of at hair follicle - Furuncles (boil) - often start at the break of hair follicle but can be in other areas; hot, tender, low fever - Carbuncle confluence of boils - Impetigo – epidermal lesion - Thick yellowish crust (children)- easily transmittable and kids are gross, they wipe on anything - Often mixed with S. pyogenes Note: careful with fever because then Tx would be systemic antibiotics

Answer 102

• Surgical/burn wound infections - Bacteremia & endocarditis • Pneumonia (1-5%) - Sequela of influenza - Fever, cough, purulent sputum • Osteomyelitis (bone necrosis) Note: Strep. pyogenes is the more common cause of pneumonia but Staph. aureus can cause pneumonia

Answer 103

Scalded Skin Syndrome - Children

Answer 104

• Toxic shock syndrome - TSST-1 (20% S. aureus) - Elevated IL-2 & TNF levels lead to shock - Fever, macropapular rash, hypotension, vomiting, respiratory distress, irrational behaviour, multi-organ - 3% mortality - Supportative measures & antibiotics - Women and men (originally associated with super absorbent tampons) Note: Streph pyogenis 30% death - Toxic shock like syndrome toxin

Answer 105

Common cause S. aureus is responsible for 5 to 25% of all reported cases of food poisoning. Intoxication - Staphylococcal enterotoxin - Enterotoxins are heat stable! - 1- 6 hr post ingestion exhibit severe vomiting and diarrhea (up to 48 hrs) Toxins have superantigen activity and act directly on neural receptors that stimulate the vomiting center in the brain. Diagnosis: Clinical presentation (no infection) Treatment: - Hydration - Monitor/correct electrolytes Note: occurs pretty quickly because the toxins are preformed. Is self limiting because the toxin you ingested - that's it. No ingestion of bacteria will not have increasing amounts of toxin produced.

Answer 106

* Culture from abscess, lesion, sputum, blood sample * Growth on salt agar (7.5% NaCl) * Coagulase, catalase tests * Antibiotic sensitivity: esp. Methicillin Resistance! Methicillin resistance due to presence of a mutant PBP in a pathogenicity island - Hospital Acquired Methicillin Resistant S. aureus (HA-MRSA) is associated with multi-drug resistance - Community Acquired Methicillin Resistant S. aureus (CA-MRSA) is not associated with multi-drug resistance **** both were derived from different lineages.****

Answer 107

Skin Infection • Drainage, topical treatment with mupirocin - bacitracin rarely effective!! • Chronic – systemic antibiotic Focal & Systemic Infection • Methicillin sensitive – several antibiotics effective • Methicillin resistant (HA-MRSA): vancomycin (esp. TSS; some transposons can confer vancomycin resistance) Vaccine • None available

Answer 108

(only coagulase – strains) NOVOBIOCIN RESISTANCE Staphylococcus epidermidis sensitive Staphylococcus saprophyticus resistant

Answer 109

Staphylococcus epidermidis * Implanted device & urinary tract, endocarditis in intravenous drug addicts * Treatment difficult esp. with endocarditis (poor circulation, drug resistance) Staphylococcus saprophytic (found in GI) • Urinary tract (women; rare in men

Answer 110

Common Properties * Gm + cocci * Normal flora: nasopharynx, skin, GI, GU * Pairs or chains * Catalase - * Blood agar Note: Blood agar can be used to differentiate once we know gm + and catalase - as opposed to the staphylococci

Answer 111

1. a hemolytic – green “halos” ; causes a change in the Hb in RBC --> alpha hemolysis, doesn't lyse heme 2. b hemolytic – clear zone; hemolysis 3. Non hemolytic – no effect ``` BLOOD AGAR HEMOLYSIS Streptococcus pyogenes b Streptococcus agalactiae b Streptococcus bovis (a/Non) Enterococcus faecalis (a/Non) Streptococcus pneumoniae a Viridans Streptococci a ```

Answer 112

Streptococcus pyogenes A Strep throat, fasciitis, ... Streptococcus agalactiae B Neonatal sepsis, meningitis Streptococcus bovis D Endocarditis Enterococcus faecalis D Urinary, endocarditis Streptococcus pneumoniae - Pneumonia, meningitis, OM Viridian's Streptococci - Endocarditis, caries Note: Cell wall carbohydrates were grouped by specific antibodies.

Answer 113

BACITRACIN SENSITIVITY* PYR TEST Streptococcus pyogenes Sensitive + Streptococcus agalactiae Resistant - *(Sensitivity presumptive) if they have PYR PYR – L-pyrrolidonyl-b-napthalamide amino peptidase

Answer 114

Group A, b-hemolytic (GABHS) * Normal flora: Nasopharynx (5-20%), skin * Many, varied diseases

Answer 115

Antigenic/ Virulence Factors 1. M protein - dimer forming coiled coiled protein. Extends from membrane all the way out. Each monomer have multiple repeats to form the coiled regions. Very similar repeats not identical. - Antiphagocytic (binds factor H, blocks alternative complement pathway) - Elicits immune response (antigenic) 2. IgAase – destroys sIgA (adhesion) 3. C5a peptidase – blocks complement activation Note: M protein --> coiled elicits weak immune response, the opsonic Ab epitope elicits a very strong immune response is a variable region thus we can be affected more than once.

Answer 116

(SPEs) -most often because they have prophages. • SPE’s (SPE-A, SPE-B, SPE-C) Strains that carry SPE cause : Toxic Shock Like Syndrome and/or Scarlet Fever

Answer 117

Localized Infections •Pharyngitis (Strep throat) - Sore throat, fever, nausea (varies), malaise, - Adenitis, yellowish exudate - Usually self-resolving - Complications: If left untreated we can get complication and mostly come from pharyngitis: - Scarlet fever, acute rheumatic fever (ARF), - Acute glomerulonephritis (AGN) Tx is useful because will usually shorten the length of time of infection and contain the infection Note: viral strep is more common than bacterial, but if bacterial Streptococcal pyrogenes is most common.

Answer 118

* Impetigo ( often a mix Staph aureus and Streptococcal pyrogens)- Epidermal Layer * Cellulitis ** (Deeper than Erysipelas) / Erysipelas * (Dermis) - Local, rapidly spreading - Soft tissue & lymphatics - Children* & elderly - (Fever, headache, chills) ** --> immediate Tx - Complication: bacteremia ** (Because Cellulitis is in the subcutaneous fat and can spread into the fascia ---> necrotizing fasciitis or get to blood stream. - Erysipelas (distinct lining and on edge is raised) - Cellulitis (entire area may be swollen but redness is more diffuse); Tx quickly - necrotizing fasciitis "hospital gangrene" does not include the strict anaerobes and production of gas as in Gas Gangrene. Note: Sometimes cellulitis and Erysipelas may overlap. Even Gm + can cause sepsis or septic shock.

Answer 119

• Necrotizing fasciitis “Hospital Gangrene” - Destroy underlying tissue “Flesh Eating Bacteria” - Swelling, heat, tenderness, fever, mental cloudiness, bacteremia, death (25-50%) - Diagnosis: Clinical presentation & pus/blood cultures (From Clinical presentation can lead quickly to death, may not look so bad from outside but can be much worse inside) - Treatment: Penicillin & surgery (debribe, allow immune system to help) • Pneumonia

Answer 120

• Scarlet Fever (rare) - Complication of pharyngitis (SPE-strains) mostly but can result as a result of infection anywhere. - Sore throat (variable), rash, red tongue - Local infection, toxin by blood • Toxic Streptococcal Syndrome (TSLS) - Complication of erysipelas (SPE-strains) - Local infection (soft tissue), toxin by blood - Bacteremia (in some cases the bacteria may be invasive and travel in blood) , shock, multi-organ failure, - High fatality rate (30%)

Answer 121

• Acute Rheumatic Fever (ARF) - Sequela of Strep throat (3%) - Inflammation of heart, joints, CNS - M proteins ~ cardiac myosins (Ag mimicry) - Repeat attacks common and get increasing severe because with an attack by another strain the coiled-coiled regions can stay the same with different N' Ab epitope (boosting immune response everytime) - The coiled-coiled regions are weakly immunogenic but with enough Ab it can cross-react with cardiac myocyte because they also have coiled coiled regions. - N' elicits a strong immunogenic response but is only specific for that epitope. Boosting of response: The other portion of M protein can be recognized in the future although the epitope changes but the Ab made can then attack the cardiomyocytes. Tx: prophylaxis for rest of their lives b/c of coiled-coiled problem

Answer 122

• Acute Glomerulonephritis (AGN) - Sequela of Strep throat & impetigo - Inflammation & renal impairment, edema - Immune complex disease: Lattice Ab-Ag complex deposited on renal basement membrane interacting with Streptococcal pyrogens debris or material (has to be enough to make lattice) ----> renal edema - Recurrence rare

Answer 123

Treatment • Immediate (Even pharyngitis) • Penicillin Chemoprophylaxis • ARF – antibiotic (years)

Answer 124

Group B, b-hemolytic (GBS) * GU or lower GI flora (25-40% of females) * Neonatal sepsis/meningitis; post-partum sepsis * Diagnosis – Group B agglutination * Treatment – Penicillin * Prevention – Penicillin during labor (GBS +) Note: S. agalactiae is the most common cause of Neonatal sepsis/meningitis Group B Strep = GBS

Answer 125

NaCl Esculin Enterococcus faecalis + + Streptococcus bovis - + NaCl Esculin * Streptococcus pneumoniae - - * Viridans Streptococci - - * = alpha hemolysis (6. 5% NaCl) Esculin hydrolysis - Complex carbohydrate and when hydrolyzed turns black

Answer 126

Group D, a/non-hemolytic * Normal flora - GI * Endocarditis (infection/inflamation of heart) * Bacteremias (esp. colon cancer); not commonly seen but immunocompromised pt.s can be affected more often

Answer 127

“Group D”, a/non-hemolytic • E. faecalis (90%), E. faecium (10%) - E. faecalis has TGE that confers Van r, higher percentage of causing infections b/c of the resistance * Normal flora – GI, GU * Endocarditis (10%), UTI (10%), meningitis, wound infections, abdominal abscesses * Drug resistance!!!! Note: Not particularly virulent but has enhanced effects with immunocompromised patients.

Answer 128

OPTOCHIN SENSITIVITY Streptococcus bovis Resistant Enterococcus faecalis Resistant Streptococcus pneumoniae Sensitive Viridans Streptococci Resistant Note: Viridans Streptococci is large group of commensal streptococcal bacteria species

Answer 129

a-hemolytic • Normal flora: S. mutans oral (30-60%) • Dental caries & endocarditis (ask if underlying heart problem); prophylactically to pt.s who have a heart condition but endocarditis can occur to people who seem fine * Dental treatment, cleaning, vigorous brushing transient bacteremia endocarditis * Prophylaxis - antibiotics (dental treatment)

Answer 130

Streptococcus pneumonia is major cause of meningitis in children and adults; Streptococcus agalactiae is major cause of meningitis infants a-hemolytic * Diplococcus * OptochinS; Bile soluble (activates autolysis in the cell envelop of Streptococcus pneumoniae ) * Normal flora: nasopharynx (5-70%) goes up in winter * Antiphagocytic Capsule: 23/85 types virulent (responsible for ~ 85% of disease) Note: 85 different strains with structural differences in capsules. 23 of them are responsible about about 85% of disease. Note: purified capsule is the basis of a vaccination. Thus we have to isolate many variations of capsules.

Answer 131

• Pneumonia (Lobar) - Sequela of upper respiratory tract infection - Sudden shaking chill & rapid, high fever - Chest pain, cough, rusty-colored sputum - 500,000 cases/yr in US (40,000 deaths) • Otitis media (mostly for kids less than 5) - Sequela of upper respiratory tract infection - > 50% of acute otitis media (>107 visits/yr) - Children (poor drainage) • Meningitis (see Bacteria of CNS) Note: After age of 5 we get a change in the size of the ear canal --> normally due to poor drainage.

Answer 132

• Aerosol spread (droplet) • Risk: Asplenic individuals, sickle cell anemia, alcoholism, 65 yrs • Congugate vaccine -

Answer 133

Informational

Answer 134

a. Capsule (variable) b. Fibronecting binding protein c. Plasma clumping factor – binds fibrinogen (aggregates Staph and prevents phagocytosis) d. Protein A (only S. aureus) – linked to peptidoglycan, binds Fc of IgG1, IgG2 and IgG4 and prevents phagocytosis e. Catalase – counteract PMN’s f. Coagulase – clotting (poor penetration by WBC’s) g. Hemolysins: alpha toxin – transmembrane channel, dermatonecrosis, and lethality; 3 other hemolysins - may be cytotoxic for a variety of cells h. Leukocidin – K+ channel, products capable of killing granulocytes and macrophages i. Phospholipase – digests fats (boils) j. Hyaluronidase – hydrolyze connective tissue k. Staphylokinase (fibrinolysin) – converts plaminogen to plasmin, which hydrolyses fibrin l. -lactamase – narrow spectrum, but 90% of strains m. Toxic Shock Syndrome Toxin (TSST-1), pyrogenic toxin associated with toxic shock syndrome, superantigen, 20% S. aureus strains n. Exfoliative toxin – desmosomal proteases cause intraepithelial separation of the skin in Scalded Skin Syndrome, plasmid encoded o. Enterotoxins – Food poisoning, heat stable superantigen, intoxication, phage encoded

Answer 135

cultivation on blood agar with growth often enhanced by 2 to 10% carbon dioxide also, fermentation on mannitol salt agar, testing for coagulase and catalase, antibiotic sensitivity is routine. Treatment: Topical treatment with mupirocin and drainage is usually effective for local (skin) infections. Systemic infections may require i.v. synthetic, penicillinase resistant pencillin or cephalosporin (e.g., methicillin for systemic, middle ear). Because of the large number of staphylococcal phages and the presence of plasmids carrying resistance markers, patterns of sensitivity change quickly. Methicillin Resistant Staphalococcus aureus (MRSA) is a problem in nosocomial infections and multi-drug resistance has been observed. In the last few years, vancomycin resistance has been recorded, potentially removing our last magic bullet. Staph isolate must be tested for antibiotic sensitivity.

Answer 136

Gram-positive, facultative cocci which lack catalase and which grow in chains in a fluid environment, and require enriched media (blood agar) for growth. Growth often enhanced by presence of 2 to 10% carbon dioxide.

Answer 137

a. Capsule (variable) b. M protein – antiphagocytic (binds factor H, blocks alternative complement pathway), but elicits immune response (antigenic) c. Streptolysin (S & O) - PMNs d. IgAase – destroys sIgA (adhesion) e. C5a peptidase – blocks complement activation f. Streptokinase dissolves fibrin clots [Purified streptokinase is used in early stage treatments of coronary infarcts] g. Hyaluronidase - breaks down hyaluronic acid; DNAse h. Leukocidin - kills PMNs i. Pyrogenic exotoxins which share sequence and biologic similarity (superantigens) to those produced by staphylococcal strains. These include erythrogenic toxin (causes scarlet fever rash) and toxin that causes Toxic Shock Like Syndrome

Answer 138

Streptococcus pneumonia Note: there are several other mostly gram negative bacteria that produce the same or similar symptoms. - Haemophilus influenzae, Moraxella (Branhamella) catarrhalis, Legionella pneumophila, Klebsiellapneumoniae, Pseudomonas aeruginosa. Less severe –Mycoplasmapneumoniaewhich has no cell wall –Chlamydia pneumonia and Chlamydia psittaci-Obligate intracellular bacteria

Answer 139

A. Differential diagnosis of bacterial vs. viral infection can be difficult B. Age-based epidemiology and patient history are important as there are different frequencies in different groups (age, mechanism of uptake of organism, seasonal or periodic population variation in prevalence of particular infections, immunocompromised states, nosocomial infections) C. Modes of acquisition - prior colonization, inhalation or aspiration of organisms from ear, respiratory tract or esophageal reflux; without normal clearing by immune system

Answer 140

A. Causes 60% of all pneumonias B. Gram positive, α hemolytic, encapsulated, diplococcus, sensitive to optochin C. Not classified by Lancefield classifications D. Carried in nasopharynx in ~15% of healthy population, higher in children E. Vaccines - Prevenar® and Pneumovax®

Answer 141

A. Its name was based on erroneous proposal that it was responsible for the 1892 influenza pandemic, actually caused common secondary infection B. Obligate parasite, fastidious growth requirements – Grows on Chocolate agar which contains Hemin (factor X) and NAD (factor V)) or TSA agar supplemented with these compounds. C. Disease: Pediatric - Meningitis (50%), Pneumonia (15%), other systemic (35%) D. Diagnosis – Gram stain of an infected body fluid may demonstrate small gram-negative coccobacilli suggestive of invasive Heamophilus disease. E. Polysaccharide capsule defines 6 serotypes (a-f); Disease from Type b the most common (Hib)-Polyribosylribitol phosphate-PrP a. A virulence factor F. IgA protease and neuraminidase produced G. Passive protection of infants during first 6 months provided by transplacental and breastfeeding-acquired IgG. Peak attack rates occur at 6-7 months of age, declining thereafter. Hib disease is uncommon beyond 5 years of age. The age distribution is likely due to acquisition of natural immunity due to transient exposure to organism without disease. H. Vaccine - Antibodies to protein conjugated Hib capsular polysaccharide are protective, 99% reduction of incidence where utilized I. Prevaccination, most invasive disease was due to Heamophilus influenzae type b. Currently, Hib found only in unvaccinated individuals (1 case/105 children US). Most Heamophilus disease now due to type a or untypable unencapsulated forms. J. Treatment with cephalosporins as ampicillin resistance is common. Hospitalization required.

Answer 142

A. Ranks third as cause of pediatric otitis media. Also causes sinusitis in children and of lower respiratory tract infections in adults, especially those with underlying chest disease. Invasive infection is uncommon. B. Carriage rates of M. catarrhalis are high (~50%) in children and in the elderly, but it is present as commensal in only ~5% adults. Transmission is believed to be due to direct contact with contaminated secretions by droplets. C. Gram negative diplococcus - once classified as Neisseria based on Gram stain and positive oxidase test D. Approximately 95% of strains are β-lactamase positive (cannot use Penicillin). E. Produces lipopolysaccharide endotoxin similar to that found in the Neisseria species. Some strains have pili or fimbriae, which may aid adherence to the respiratory epithelium.

Answer 143

A. Causes Legionnaire’s disease (LD) or Legionellosis, a frequently fatal pneumonia and Pontiac fever, a less severe self-resolving flu-like illness B. Pathogen “emerged” in 1976 due to Philadelphia hotel infectious cluster and investigations by the CDC into its cause. Found to be a significant cause of pneumonias previously believed to be viral. C. Considered opportunistic pathogen. Typically, those who become ill are of advanced age and have sustained damage to the host defenses that normally protect lungs from infection. Common risk factors for legionellosis are cigarette smoking, emphysema or other chronic lung diseases, lung and hematologic malignancies, and clinical immunosuppression or cytotoxic chemotherapy. D. Aerobic gram negative pleomorphic often motile rod. E. Amoebae are reservoir and perhaps more normal host. Commonly transmitted through contaminated droplets produced by normal plumbing, misters, hot tubs or air conditioning water cooling towers which harbor the amoeba. 2 - 10 day incubation period. No documented person to person transmission F. Estimated ~20,000 cases/year in US, but only ~1000 reported. Most cases of LD are sporadic; ~25% are nosocomial and 10%-20% can be linked to outbreaks such as the one that lead to its “discovery” and naming. Pontiac fever is usually recognized only during LD outbreaks. Death occurs in 10%-15% of LD G. Intracellular replication of bacteria in amoebae and in alveolar macrophages very similar. They divide in vesicles that are modified to resist fusion with lysosomes. Bacteria become short and motile prior to release from host cell. Temperature (warm water in air conditioning tanks, hot tubs, etc.) may contribute to turning on genes, which contribute to increased pathogenesis. H. Pontiac fever patients become seropositive for Legionella pneumophila but the organism cannot be isolated from them. I. Other Legionella species may be significant contributing agents to community acquired pneumonias; most serological tests are specific to L. pneumophila. (More than 40 species are now known, half isolated from patients). J. Diagnosis using fluorescent antibodies to stain sputum, culture and detection of antibody in blood K. Treatment with macrophage penetrating drugs – Macrolides, Tetracyclines or Quinolines

Answer 144

A. Gram negative, rapidly growing, usually motile with polar flagella, earthy smell in culture, minimal nutritional requirements Ubiquitous soil organism, found in 2% of healthy adults Oxidase positive, resistant to 1st and 2nd generation penicillins and vancomycin, sensitive to fluoroquinolines and streptomycin B. Considered an opportunistic pathogen 1. Major cause of morbidity and mortality in CF patients May bind better to CFTR defective epithelial cells Very difficult to eradicate completely in CF patients 2. Common catheter contaminant 3. Establishment of infection The mucoid exopolysaccharide (alginate) slime produced by P. aeruginosa forms a matrix/biofilm which anchors the bacteria and insulates it from host defenses. Nonmucoid bacteria that are easier to eradicate with antibiotics may precede mucoid producing ones. Other important virulence factors - Secreted protease (elastin) and ADP ribosylases (exotoxin A and exoenzyme S) and endotoxin (LPS) Proteolytic necrotic destruction a hallmark of Pseudomonas infection

Answer 145

Burkholderia cepacia produces cepacia syndrome which is lethal especially for CF patients. Burkholderia pseudomallei causes an acute pneumonia called melioidosis, a zoonotic associated with rat infestations Stenotrophomonas (nosocomial pneumonia, primary bacteremia, sepsis and urinary tract infections).

Answer 146

Enterobacteriacae - Closely related to E. col, encapsulated gram negative rod, facultative anaerobe enabling it to cause lung abscesses. Considered opportunistic, nosocomial infection with a high mortality rate (>25% even with antibiotic treatment). Mortality usually due to disseminated bacteremia. Insidious lung infection characterized by chest pain, thick, bloody sputum, lung abscesses, tissue necrosis and septicemia Capsule protects from phagocytosis Found ubiquitously in ground water, sewage, soil Other pathogenic species (K. oxytoca, K. ozaenae, K. rhinoscleromatis and group 47) Diagnosis by gram stain, sputum culture and API strip, PCR. Treatment with penicillin or cephalosporin unless resistant

Answer 147

Smallest “free-living” organism, found in filtrates that exclude most bacteria Lacks rigid cell wall (no peptidoglycan) Membranes contain sterols which are required for growth Distinctive “fried egg” colony shape is produced by gliding motility. Other pathogenic mycoplasma – M.hominis, U. urealyticum: B. Mycoplasma pneumoniae causes mild disease such as otitis media, sore throat, pharyngitis, and tracheitis. 5-10% of those infected develop severe bronchitis or atypical “walking pneumonia”. Occasional CNS involvement or rash (erythema multiforme) observed. C. Epidemiology: 2 million cases/yr US requiring ~100,000 hospitalizations; 20% of all pneumonias. Community reservoirs - young children, also very common in adolescents, college dorms, military barracks. Patients with sickle cell disease are very vulnerable. Outbreaks every 5-7 years believed to be due to loss of immunity. D. Pathogenesis: attachment of protein P1 at tip structure binds to polysaccharide receptor of respiratory mucosa. Organism migrates to and grows in spaces between epithelial cells, paralyzing respiratory cilia and causing an inflammatory response. Variable surface antigen-undergoes both phase and length variation. Short form of surface protein proposed to be more resistance to complement mediated lysis. Monocytes surround infected bronchi and bronchioles producing broncho-pneumonia. Usually does not involve lower lobes. E. Diagnosis: Based on symptoms: 2-3 week incubation period prior to symptoms, atypical pneumonia, less severe “walking pneumonia” that does not respond to penicillin but does respond to antibiotics that do not target the cell wall. Confirming diagnosis usually for epidemiological purposes requires special media and takes too long to be relevant for patient care. Fluorescent antibody can also be used to look for the organism in throat swabs or sputum samples. Alternatively, PCR tests can also be used. In addition, there is a quick bedside “serum cold agglutination test”. A nonspecific test for M. pneumoniae, but findings are positive in only 50-70% of patients after 7-10 days of infection. Test can be performed by partially filling a purple-top tube with blood and placing it in ice; a positive finding is one in which "grains of sand" appear on the glass portion of the tube. Cold agglutinin tests can be done by diagnostic laboratories. A negative result does not exclude infection, and this test may be affected by cross-reactions with other pathogens, such as adenovirus, Epstein-Barr, and measles viruses. Treatment - Erythromycin (Zithromax) and tetracycline. Since these organisms lack a cell wall β-lactam antibiotics have no effect.

Answer 148

A. Obligate intracellular parasite. Small (0.2 micron extracellular [EB]) and large (0.8 micron intracellular [RB]) forms, Gram negative contains LPS but does not contain typical peptidoglycan in the cell wall. B. Causes atypical pneumonia, bronchitis, pharyngitis, sinusitis, fevers. Incubation period ~30 days. C. Possibly the most prevalent chlamydial pathogen in the population. 50% of U.S. population seropositive by age 20, increases to >80% with age. D. Chlamydiae undergo differentiation. Elementary bodies (EB), infective transit form upon uptake change to reticulate bodies (RB), the intracellular dividing form. EBs are small (0.2 micron) and have distinctive shape. They interact with specific receptors to gain cell entry. RBs are larger (0.8 micron), replicate inside phagosomes and are converted to EBs before exiting. Chlamydia inhibits phago-lysosomal fusion and use host metabolites for growth. They import ATP directly by exchanging it with ADP resulting in net energy gain. Small genome indicative of obligate intracellular parasites using host functions E. Possible association of prior infection with atherosclerosis and inflammatory arthritis. Suggestion that inflammatory response to organism damages blood vessels. F. Diagnosis by looking for antibody to organism or PCR on infected material. G. Treatment with protein synthesis inhibitor antibiotics, prolonged high doses of tetracycline or macrolides (erythromycin). These organisms are resistant to sulfa drugs and β-lactam antibiotics.

Answer 149

A. Psittacosis, Parrot Fever or Ornithosis, a flu like systemic infection (fever, headache, and atypical pneumonia). B. Thought to be acquired from birds, poultry and parrots. Occasionally can be acquired from farm animals. 2 week incubation period. Psittacosis can cause sepsis, placental infection, and fetal mortality. Fewer than 50 cases reported cases/yr in US. C. Obligate intracellular parasite similar to C. pneumoniae (see above for diagnosis and treatment).

Answer 150

a. Suppurative infections: Skin infections including folliculitis; furuncles (boils) – hot, tender, low fever; and carbuncles (confluence of boils); impetigo – epidermal lesion with thick, yellowish crust forming after clear pustules burst (easily spread); surgical wound infections (stitch abscess), eye, middle ear, burn wound infections, nursery epidemics or neonatal infections; pneumonia (~Strep pneumonia, less common, 1-5%); osteomyelitis b. Toxic infections: scalded skin syndrome; toxic shock syndrome. Scalded Skin Syndrome - children

Answer 151

Coagulase negative Staph may cause infections: localized skin abscesses; endocarditis in drug addicts; post cardiac surgery; urinary tract infections and chronic bacteremia in hydrocephalics with indwelling shunts; urinary tract infections. Often difficult to treat because of antibiotic resistance. (Vancomycin is current antibiotic of choice.)

Answer 152

•Caused by viruses, bacteria, fungi •6thleading cause of death in US –~25 deaths/100,000 people (~70,000/yr) –80% of these are people >65 yrs old (~50,000/yr) •WHO estimates that 4 million children under age 5 die annually from pneumonia. –Most deaths are in non-industrialized nations where deaths due to bacterial pneumonias are common. –In industrialized nations, deaths due to viral pneumonias more common

Answer 153

Each requires different protocol of treatment Classification of Pneumonia: 1. CAP, community-acquired pneumonia - Bacterial - Viral 2. HAP, hospital-acquired pneumonia - HCAP, health care–associated pneumonia; - VAP, ventilator-associated pneumonia.

Answer 154

Lower respiratory infection of bronchioles or alveoli. A consolidation in the lung * Increased mucous production, migration of neutrophils and macrophages to alveoli * Symptoms –“ooooh I feel soooo awful”(malaise), shortness of breath (dyspnea), cough, fever (febrile), fluid in the lungs (pleurisy), abnormal chest X-ray, blue finger tips

Answer 155

Less than 2 years old 60% viral (mostly RSV) 40% bacterial Greater than 2 years old 70% bacterial (~2/3 Pneumococcus) 30% viral

Answer 156

1. Streptococcus pneumoniae- Lobar pneumonia, Gm+ encapsulated 2. Mycoplasma pneumoniae -atypical “walking” pneumonia, no cell wall) 3. Chlamydia pneumoniae -(obligate intracellular pathogen, atypical pneumonia) Haemophilus influenzaetype b –effective vaccine, PRP capsule Moraxella catarrhalis prevalent carriage/kids and elderly, mostly Penicillin resistant Gm-diplococcus Legionella pneumophila -opportunist, grows in amoeba Klebsiella pneumoniae -opportunist, Gm-encapsulated Pseudomonas aeruginosa opportunist/CF patients Gm- Chlamydia psitacci (Parrot Fever or Ornithosis) -birds

Answer 157

Inversely proportional. E.g Streptococcus pneumonias 74% : 12.3% E.g Pseudomonas aeruginosa 0.3% 61.1%

Answer 158

Development of Bacterial Pneumonia ``` Adherence to cells of the oropharnyx  Bacterial colonization  Aspiration into the lung  Escape from normal lung defenses and (re)colonization ---> (massive inflammatory response --> fluid enters lungs --> now we get a mechanical impedance to breath) ``` Note: can go from Adherence to cells of the oropharynx ---> Aspiration into the lung

Answer 159

Colonization of upper airways with pathogens -alcoholics, antibiotic treatment Cough or glottic closure Abnormal or absent ciliary motion, trauma or tracheostomy Pre-existing lung disease-asthma, COPD, cystic fibrosis Immune deficiency of neutrophils or alveolar macrophages

Answer 160

Streptococcus pneumonia * The cause of 60% of pneumonias * Pneumococcus * Typical pneumonia * Gram positive, encapsulated, diplococci, α-haemolytic, sensitive to optochin * Treat with β-lactams (penicillin) or macros Prevention: polyvalent vaccine : Prevnar and Pneumovax Note: Gram positive, encapsulated was the genetic trait that was able to be inherited in offspring --> There's DNA discovery!

Answer 161

Mostly gram negative and cell wall less organisms

Answer 162

Serotype b or HiB-The most pathogenic, responsible for most infections Formerly a major problem for infants 6 mo.–5 yrs., HiBPRP capsular vaccine (conjugated vaccine which has made this much less of a threat) largely eliminated the threat in developed countries Diagnosis -Grows on chocolate agar (boiled blood) or regular blood agar supplemented with NAD (factor V) and Hemin(factor X) Treatment -Augmentin (amoxicillin + clavulanate), new generation cephalosporins or macrolides

Answer 163

Gram negative diplococcus Originally classified as Neisseria, Later called Branhamella Considered a commensal Carriage rates high in children and in the elderly Also causes upper respiratory infections Ranks third as cause of otitis media Causes sinusitis and laryngitis chronic bronchitis in smokers Lab identification - Gram negative diplococcus - Oxidase positive like Neisseria - Metabolic tests used to distinguish it from Neisseria Treatment: - 2nd or 3rd generation cephalosporin's or macrolides (e.g. Azithromycin/Z-pack) - Resistant to PENICILLIN and VANCOMYCIN (GM -) 90% of isolates produce β-lactamase Note: that is oxidase + thus used to be called Neisseria but then the name change to Branhamella because it was realized it has other metabolic needs and then the name changed to Moraxella

Answer 164

Contaminated water source. Legionnaire grows in amoebas and macrophages. Airconditioning was more prevalent in 1976. - More typical is the sporadic case

Answer 165

``` –Severe pneumonia, incubation period of 2-10 days. –High mortality (~15% fatal) –In the US, only 1000 cases/yr reported –10,000 cases/yr estimated –Sporadic cases rarely recognized ``` •Opportunistic disease in immunocompromised individuals only; most likely won't affect healthy individuals –Heavy smoking, steroid treatment, age •PONTIAC FEVER -A non-pneumonic febrile illness that is not life threatening. –Onset is 1–2 days after exposure –Named after disease cluster that appeared that year in Pontiac, MI building. Air Conditioner water caused disease in Guinea Pigs Note: at first not previously recognized as infections due to Koch's postulate

Answer 166

Gram negative, hard to stain, thin, often motile pleomorphic rods 0.5x 2-20  Facultative intracellular organism –grows in amoeba (Acanthamoeba castellani) in the wild and within macrophages during human infection Not virulent when grown on nutrient agar Intracellular or newly released virulent forms have short rod and are highly motile Hard to stain and not virulent when on agar thus hard to do Koch's postulate. Note: Pleomorphism, in microbiology, is the ability of some bacteria to alter their shape or size in response to environmental conditions.

Answer 167

Bacteria grows in amoeba above 25°C, killed by amoeba below 20°C Following several rounds of intracellular replication bacteria converts to virulent motile form capable of extracellular survival and transmission to new host If aspirated into susceptible lung, L. pneumophila taken up by alveolar macrophages where they replicate and cause pneumonia in the absence of a robust cell-mediated immune response.

Answer 168

1. Bacterium engulfed by coiled phagosome, becomes internalized within endosomes that do not fuse with lysosome and become surrounded by rough ER. 2. Bacteria replicate within endosomes as less virulent nonmotile form. When nutrients are depleted it converts to the motile virulent form and lyse the cell to escape. 3. Disease due to massive inflammatory response.

Answer 169

•Lab Identification: –Fluorescent Abs –microscopic detection of organism in sputum –Culture on special medium –Serological detection of antibody in blood •Treatment: –Antibiotics that penetrate macrophages: Erythromycin, Tetracycline or Ciprofloxacin Note: Penicillin doesn't penetrate macrophage.

Answer 170

Enterobacteriacae that causes pneumonia and UTIs Gram negative, encapsulated rod Facultative anaerobe- will cause absecess that wall of from lung and thus is in an anaerobic environment. Lysing of this absecess will release huge amounts of LPS causing sepsis and tissue necrosis. -May be in normal flora (very small amounts) in lungs in small amount and is an opportunistic pathogen many serotypes: - LPS –O - Capsule -K Note: producing mucoid colonies with Lac+ giving a pink color on MacConkey agar

Answer 171

Insidious infection: chest pain, thick, bloody sputum, lung abscesses, tissue necrosis and septicemia. Opportunistic, often secondary infection Can be isolated from respiratory tract in ~5% of general populations High fatality rate ~ 50% - if abscess lysis Other clinically significant Klebsiallae: K. oxytoca, K. ozaenae, K. rhinoscleromatis, group 47

Answer 172

An opportunist, causing pneumonias and systemic infections Associated with catheters related infections and immunodeficiencies Chronic infections in cystic fibrosis patients Also otitis externa (Swimmer’s ear)

Answer 173

Gram negative, oxidasepositive, motile rod with polar flagella Extremely fast growing, minimal growth requirements Colonies have a grape-like or fruity smell, often blue Virulence factors: Adhesins-pilithat bind receptors on epithelial cells and flagellarproteins that bind to airway mucins Produces alginate aka SLIME, a gelatinous polysaccharide, required for biofilmformation that makes organism 50X more resistant to host defenses and antibiotics Produces ADP ribosylases(exotoxinA and exoenzymeS which inhibits cellular protein synthesis) and endotoxin(LPS). Secretes protease (elastin), helps damage tissue for colonization, proteolyticnecrotic destruction is a hallmark of infection Note: bandages of WWI were turning blue

Answer 174

Prior respiratory infection believed to damage tissue leaving it vulnerable to colonization by Pseudomonas. CF patient airways and lungs almost always infected with alginate/slime biofilm producing strains Burkholderia cepacia complex (BCC)–originally classified as a Pseudomonas. Causes Cepacia Syndrome in CF patients. Like Pseudomonas it is motile, Gm-and produces biofilm

Answer 175

Motile Gm-organisms, often associated with biofilm production Burkholderia cepacia –Cepacia in CF patients Burkholderia mallei –Glanders, zoonotic Burkholderia pseudomallei –Melioidosis, glanders-like illness common in SE Asia, associated with contaminated water

Answer 176

Atypical or walking pneumonia - highly communicable disease Causes otitis media and pharyngitis which can turn into bronchitis and “walking pneumonia” - not as sick as real pneumonia and thus you can walk around with it. Not severe disease but very common. Fever, headache, malaise for several days before onset of respiratory symptoms Non-productive cough, later may become productive X-rays can reveal diffuse bronchopneumonia Presumptive diagnosis based on severity and lack of responsiveness to penicillin followed by responsiveness to non β-lactam antibiotics

Answer 177

2 million cases/yr in US 100,000 hospitalizations Spread by droplets where people are in close contact so clusters especially common in college dorms, army barracks and in school age kids Epidemic infections every 4-7 years, thought to reflect 2-10 year acquired immunity. Crowd source immunity. Large numbers of people get infected get Ab and only years later does the Ab amount dilutes and can be infected again after years of initial crowd exposure.

Answer 178

Bacteria that lacks a cell wall and contains sterols in plasma membrane. Gets sterols from host. No rigid cell wall, cell shaped maintained by primitive cytoskeleton Sterol containing cell membranes, sterols required for growth of some species Appears to be obligate free living parasite –smallest known bacteria, first thought to be a virus Small genomes believed to have arisen by gene deletions from ancestral species M. pneumoniae,M. genitaliumand M. hominis and Ureaplasma urealyticum

Answer 179

Evades immune response with variable surface antigen-undergoes both phase and length variation. Enters airways and adheres (the tip has adhesins) to epithelial and disables the cilia and we get a cough (dry) to try and clear it out.

Answer 180

Mycoplasma have a tip structure containing adhesin protein P1 that binds to a specific host receptor protein Organisms slide tips first into the interstitial spaces between cells in the ciliated epithelium and stop cilia from beating Organism replicates in inter-cellular space within epithelium ``` Produces biofilms (which causes the fried egg appearance in culture) enabling drug and complement resistance tip ```

Answer 181

Serum cold agglutination (spin cells down get ride of cells and allow to sit in cold (ice bath) and will see agglutinate) is a nonspecific test for M pneumoniae, but findings are positive in only 50-70% of patients after 7-10 days of infection. Slow growing - requires special medium and produces FRIED EGG SHAPED COLONIES due to biofilm Diagnosis can be confirmed by staining sputum with fluorescent antibody or carrying out PCR for mycoplasma genes

Answer 182

* Erythromycin, tetracycline or quinolines | * Never β-lactam or cephalosporin

Answer 183

Another cause of atypical “Walking”pneumonia where most cases go undiagnosed. Disease: fever, sore throat, nonproductive cough, rales, myalgia and frontal headache, pneumonia, CNS symptoms Accounts for ~10% of all community acquired pneumonias, common in young adults and adults >60 years old. 50% of US population seropositive at age 20, percentage increases to >80% are seropositive

Answer 184

Obligate intracellular gram negative bacteria Energy parasites acquiring ATP and nucleotides from the host cell Biphasic life cycle Elementary body (EB) ↔Reticulate body (RB) EB (extracellular infectious elemental body) smaller form responsible for transmitting infections to new cells RB (replicative elemental body) larger metabolically active form that replicates within macrophages C. trachomatis causes trachoma and urinary tract infections

Answer 185

Infectious EB gets into cell and avoids the fusion of phagosome with lysosome. Then converts to metabolically active RB inside the phagosome. The RB replicate and then condense into EB to be released from cell and infect another cell.

Answer 186

Diagnosis: fluorescent antibody staining and demonstrating that macrophages contain inclusion bodies Treatment: Tetracycline or erythromycin (Zithromax) Sulfa drugs and β-lactam antibiotics not very effective

Answer 187

Chlamydia pneumoniae may be linked to Atherosclerosis, Inflammatory Arthritis and Alzheimer’s Disease 60% of heart patients had antibodies to C. pneumoniae vs. 20% in the normal control population People testing positive for C. pneumonias antibodies had 2X the amount of carotid artery thickening vs. seronegative population Diseased coronary arteries show electron-microscopic evidence of chlamydia infection Patients on tetracycline or quinolone had a lower frequency of heart attacks --Antibiotics that do not affect chlamydia did not have this effect. Note: linkage association because 80% of us have been infected by C. pneumoniae

Answer 188

Theory: Inflammatory response to organism damages blood vessels, joints and nerves leading to atherosclerosis, arthritis and Alzheimer’s. Prevalence makes all of the above questionable making it difficult to prove causality

Answer 189

•Cause of psittacosis, Parrot fever or ornithosis –Systemic infection with pneumonia, hepatitis and endocarditis –Often asymptomatic •Spread by inhalation –Bird feces –Risk groups –pet shop employees, poultry workers * Birds usually are not sick * Lower incidence believed to be due to antibiotics in poultry feed stocks

Answer 190

All mycobacterial human pathogens are aerobic, slow-growing, intracellular bacteria with lipid-rich cell walls. They are Gram-positive, and acid-fast. They generally do not produce toxins or other overt virulence factors. Instead, they cause disease by provoking a similar GRANULOMATOUS pathological immune response in the host.

Answer 191

1. Morphology and cell wall structure a. Elongated thin rods b. Most significant characteristic: Lipid-rich cell wall c. Key cell wall components: mycelia (MYCOLIC) acids d. Gram +, Non-motile, non-spore-forming Cell Wall Lipid-rich: mycolic Acids, and other lipids Lipoarabinomannan (LAM) N-glycolylmuramic acid (NGAM) in peptidoglycan Fatty cell wall blocks destaining of stained cells (“acid-fast”) 2. Growth and staining characteristics a. Peculiar growth and staining characteristics are a direct result of lipid-rich cell walls b. Slow-growing probably because of cell-wall barrier to nutrient uptake c. Acid-fast staining because lipids prevent decolorization

Answer 192

1. Ancient plague: evidence in preserved human remains a. TB epidemic in Europe in 18th and 19th centuries concomitant with industrialization b. Associated with crowding 2. World-wide: a. Up to 1/3rd of humans infected; 30 million have active TB; 8.8 million new cases in 2003 b. Current incidence levels: highest in Asia, but appreciable around the world 3. In the USA: a. Steady decline of new cases through 1980s b. Brief resurgence in the late 1980s through early 1990s coincident with spread of AIDS c. Current incidence levels are around 20,000 new cases/year

Answer 193

Mode of Infection and Consequences of Infection 1. Spread by droplet nuclei containing Mtb (must be active) 2. Droplet nuclei are expelled by coughing, sneezing, speaking or singing by person with active TB 3. Close contacts at highest risk E. Pathogenic Mechanisms 1. TB is a disease caused by a pathological host response to Mtb; Mtb makes no toxins or virulence factors 2. Consequences of Exposure to Mtb a. Inhaled Mtb are initially confined to a localized area of inflammation (“granuloma”) b. Only 5% of infected individuals develop disease concomitant with active Mtb replication; 95% are asymptomatic; 5% of the asymptomatically infected persons can later suffer “reactivation TB”., so that an aggregate total of 10% of infected individuals suffer TB.

Answer 194

Immunity to Mtb a. High natural immunity (95% of infected individuals are asymptomatic) i. Protective response destroys most Mtb by generating oxygen and nitrogen radicals b. Cell-mediated immunity develops 2-6 weeks of exposure i. Inhaled Mtb is engulfed by “unactivated” macrophage, lead to production of IL-1, TNF and other cytokines ii. IL-1 and other cytokines activate T-cells iii. Activated T-cells recognize Mtb-antigens on infected macrophages, and activate the macrophages to produce oxygen and nitrogen free radicals iv. Cytotoxic lymphocytes (CTL) destroy infected macrophage, but paradoxically release viable Mtb, allowing dissemination c. A delayed-type hypersensitivity (DTH) to Mtb antigens develops; the severity of the DTH determines disease outcome. pathological hypersensitivity that ultimately leads to tissue damage characteristic of TB i. In asymptomatically infected individuals, Mtb replication and dissemination are limited. Mtb is “walled-off”, most Mtb, but not all, are killed ii. In untreated “primary TB” individuals, due to more severe DTH, tissue destruction and CTL-mediated cytolysis of infected macrophage continues unchecked (“caseating necrosis”), allowing cycles of Mtb replication, dissemination, and further DTH-mediated caveating necrosis 4. Reactivation TB occurs when person with dormant Mtb is temporarily immunosuppressed, and follows a course similar to “primary TB” Note: An ability to survive and multiply within macrophages is the key to its virulence. 95% of people with the activated macrophages will become latent and of 95% of latent 95% will be asymptomatic. Of the 5% following macrophage activation we get primary TB. Of the 5% of latent we get reactivation TB. With both active forms of TB we get casting necrosis via DTH mediation tissue destruction and down stream we get dissemination due to the rapid TB replication and release.

Answer 195

Delayed type hypersensitivity - Delayed hypersensitivity reactions are inflammatory reactions initiated by mononuclear leukocytes (lymphocytes and monocytes). The term delayed is used to differentiate a secondary cellular response, which appears 48-72 hours after antigen exposure, from an immediate hypersensitivity response, which generally appears within 12 minutes of an antigen challenge. These reactions are mediated by T cells and monocytes/macrophages rather than by antibodies. They are also termed type IV hypersensitivity reactions.

Answer 196

Military Tuberculosis a. A disseminated form characterized by a large number of small (“millet-like”) nodules throughout the body including lungs, liver, pancreas, kidney, brain and bones b. Epidemiology: 1-3% of immune competent individuals with TB; more in immune-compromised patients with TB c. Mechanism: Erosion of a blood vessel by caseating necrosis in the lung spreads Mtb through the bloodstream and lymphatic circulation

Answer 197

1. Primary TB a. Mild symptoms; fever, malaise, “Ghon complex” calcified healed tubercles. 2. Reactivation TB (or untreated primary TB) a. Prolonged Cough, hemoptysis, chest pain b. Fever, severe weight loss and fatigue, malaise c. X-ray: infiltrates - Opacification of airspaces within the lung parenchyma. Consolidation or infiltrate can be dense or patchy and might have irregular, ill-defined, or hazy borders. Cavities indicating tissue destruction d. Death in 2-5 years (if untreated) 3. Miliary TB a. Mild symptoms: fever, wait loss, night sweats, cough, splenomegaly Note: Ghon's complex is a lesion seen in the lung that is caused by tuberculosis. The lesions consist of a calcified focus of infection and an associated lymph node. These lesions are particularly common in children and can retain viable bacteria, so are sources of long-term infection and may be involved in reactivation of the disease in later life. However In most persons, the granulomatous disease will not progress. Over time, the granulomas decrease in size and can calcify, leaving a focal calcified spot on a chest radiograph that suggests remote granulomatous disease.

Answer 198

1. Tuberculin (PPD) test a. Measures DTH to PPD (purified protein derivative) i. Area of induration must be >10 mm to be positive ii. Indicates prior infection, not necessarily active TB iii. Limitations (a) BCG vaccinated persons can be PPD+ve (b) Severely immune-compromised individuals may be anergic (no reaction even though they have TB) 2. Lab Diagnosis a. Acid-fast stain of sputum b. Culture for identification and drug –sensitivity testing 3. Radiographic and imaging

Answer 199

1. Long-term combination antibiotic therapy: First and second line TB drugs 2. Complications a. Patient compliance; “Directly Observed Treatment” b. Multi-Drug Resistant (MDR) strains 3. Prevention a. Reportable disease b. Contact-tracing, PPD testing and prophylaxis c. BCG vaccination: not done in USA because of questions on effectiveness

Answer 200

1. Morphology, growth, epidemiology, pathogenesis a. Acid-fast, slow growing, obligatory intracellular parasite (cannot be grown in artificial medium; can be grown in the armadillo) b. Reservoir is human; possible that the armadillo is also infected, but not responsible for spread of leprosy c. Not highly infectious—requires prolonged contact (reservoir=humans) d. Infects macrophages, Schwann cells; attack on nerve cells leads to patchy anesthesia 2. Clinical presentation and classification of Leprosy a. Major types: Tuberculoid, Borderline and Lepromatous i. Tuberculoid: CMI active, characterized by macules; disease is indolent; very few bacteria ii. Lepromatous: CMI defective; massive uncontrolled growth of M. leprae; excessive skin lesions and deformations 3. Diagnosis and treatment a. Acid-fast staining and serological tests, clinical picture b. Dapsone +Rifampin 4. World-wide prevalence, and possible zoonotic connection

Answer 201

A. M. kansasii 1. Photo-chromogenic (pigmented colonies when grown in light) 2. Slow-TB like disease, very rare, probably in immune-compromised individuals B. M. avium-Intracellulare Complex (MAC) 1. Non-chromogenic 2. Slow-TB like disease, very rare, probably in immune-compromised individuals 3. Systemic disease in AIDS patients

Answer 202

Actinomycetes are a heterogenous group of Gram +ve, opportunistic bacterial pathogens with a characteristic branched filamentous growth. (Their name reflects previous mis-identification as fungi.). They cause slow inflammatory diseases such as actinomycosis and nocardiosis mostly in immune-compromised individuals. I. ACTINOMYCOSIS A. Actinomyces israelii and other spp.: morphology, growth 1. strictly anaerobic 2. Gram +ve, BUT NOT ACID-FAST B. Actinomycosis clinical presentation 1. Mucosal inflammation (predominantly cervicofacial) with surface openings (sinuses) a. Associated with tooth extraction or poor dental hygiene 2. Characteristic: “Sulfur granules”—clumps of bacteria (contain no Sulfur) C. Diagnosis and treatment 1. History, clinical picture, sulfur granules, culture 2. Penicillin G

Answer 203

A. Nocardia spp. – structure, morphology 1. Acid-fast, even if weakly so 2. Aerobic B. Major types of nocardiosis 1. Pumonary (N. asteroids): acute bronchopneumonia—mainly in immune-compromised individuals 2. Cutaneous (N. brasiliensis): pustules with sinuses; include “mycetoma” and “Madura foot” diseases C. Diagnosis and treatment 1. Gram +ve branched cells in sputum or aspirates 2. Sulfonamides

Answer 204

Tuberculin is a glycerol extract of the tubercle bacillus. Purified protein derivative (PPD) tuberculin is a precipitate of species-nonspecific molecules obtained from filtrates of sterilized, concentrated cultures. the active agent in tuberculin as a protein. A standard dose of 5 tuberculin units (TU - 0.1 ml) is injected intradermally (between the layers of dermis) and read 48 to 72 hours later [DTH] This intradermal injection is termed the Mantoux technique. A person who has been exposed to the bacteria is expected to mount an immune response in the skin containing the bacterial proteins. The reaction is read by measuring the diameter of induration (palpable raised, hardened area) across the forearm (perpendicular to the long axis) in millimeters. If there is no induration, the result should be recorded as "0 mm". Erythema (redness) should not be measured.

Answer 205

1. Stain with warm carbol fuschin; all bacteria stain red 2. De-colorize with acid-alcohol: most bacteria give up red dye; “acid-fast” bacteria do not! 3. Counter-stain with methylene blue; decolorized bacteria pickup blue stain, but acid-fast bacteria cannot bind methylene blue, and will remain red

Answer 206

Hydrophobic cell wall creates strong permeability barrier rendering mycobacteria resistant to a wide variety of antimicrobial agents. Principal contributor to hydrophobicity: mycolic acid (a fatty acid) Channel forming proteins (porins) allow hydrophilic molecules to pass through their hydrophobic cell wall. Major antigenic component is “liberated proteins”, including “tuberculin”

Answer 207

Strictly aerobic and intracellular  Reside and proliferate within macrophages  Resistant to drying and disinfectants, but not to heat  Can grow in vitro ( not all mycobacterium grow in vitro) at 37C but not at room temperature  Require enriched complex media (e.g., Lowenstein-Jensen Medium)  Slow growth (Generation time: 12-24 h; colonies: 3-6 wks). Attributed to cell-wall barrier to nutrient uptake. Clumped, rough colonies

Answer 208

TB, an ancient human plague, became rampant in Europe coincident with rapid industrialization and urbanization  “Consumption as the disease of the sensitive, artistic individual”  Chopin, Paganini, Rousseau, Goethe, Chekhov, Thoreau, Keats, Browning, Brontës etc.  1865: TB is shown to be an infectious disease (Jean-Antoine Villemin)  1882: Mtb isolation, and “Koch’s postulates” (Hermann Heinrich Robert Koch)  Disease is spread by close contact, a by-product of urbanization

Answer 209

1. The microorganism must be found in abundance in all organisms suffering from the disease, but should not be found in healthy organisms. [Exception: asymptomatic carriers] 2. The microorganism must be isolated from a diseased organism and grown in pure culture. [Exception: prions] 3. The cultured microorganism should cause disease when introduced into a healthy organism. 4. The microorganism must be re-isolated from the inoculated, diseased experimental host and identified as being identical to the original specific causative agent. Note: A prion is an infectious agent, composed entirely of protein, presumed to be the cause of the transmissible spongiform encephalopathies (TSEs).

Answer 210

1. Exposure (inhalation of droplet nuclei) 2. Uptake by macrophages, limited intracellular multiplication, granuloma formation 2a. 95% asymptomatic, halt of bacterial multiplication tubercles become calcified (Ghon Complex) 2b. 5 % primary TB, bacterial multiplication, spread, tissue damage 2a1. 90% no further symptoms 2a2. 5% Reactivation TB, bacterial multiplication, spread, tissue damage (more severe symptoms) Granuloma: will have activated macrophages, CD4/8, epitheloid cells and MTb. The granulomas of tuberculosis tend to contain NECROSIS ("caseating tubercules"), but non-necrotizing granulomas may also be present. Multinucleated giant cells with nuclei arranged like a horseshoe (Langhans giant cell) and foreign body giant cells are often present, but are not specific for tuberculosis. Note: while in granuloma rapid replication is suppressed. Epitheliod cells are activated macrophages resembling epithelial cells; Epithelioid cells are an essential characteristic of granulomas: that is to say that witho

Answer 211

Only about 10% of infected humans ultimately develop disease—indicates high natural immunity  Certain population groups are more at risk for disease  Cell-Mediated Immunity (CMI) develops 2-6 weeks after primary infection; a Delayed-Type Hypersensitivity (DTH) to Mtb antigens determines disease outcome

Answer 212

cheese-like” proteinaceous mass of dead macrophage and other cells originating in a granuloma

Answer 213

Highly disseminated form of TB: lungs, spleen, liver, kidneys, bones, brain  Numerous small (“millet-like”) caseating nodules  Mechanism: blood vessel erosion by caseating necrosis in lung; seeding of distant sites via bloodstream and lymphatic system  1%-3% of immune competent TB cases; more when immune-compromised  Mild clinical presentation  100% lethal if untreated

Answer 214

Landmark study in India (Lancet 362:507; 2003)  Smoking (cigarettes or bidis) linked to increased incidence 400% of reactivation TB  Death is 4 times more likely for smokers with TB vs. non-smokers with TB Diabetes and susceptibility to TB

Answer 215

Tuberculin Test Measures DTH to tuberculoprotein (PPD) 5 units injected intradermally After 48-72 hrs, if area of induration is >10 mm, prior INFECTION is suspected  False +ve: BCG vaccinated people; Non-TB Mycobacterial infections  False –ve: Anergy (no DTH) in immune-compromised patients (e.g., HIV); co-infections; very young or very old patients  Laboratory Diagnosis - Acid-fast bacilli in sputum or smears  - Culture confirmation required because of ubiquitous non-pathogenic mycobacteria, but also to determine antibiotic sensitivity  - MTB/RIF rapid PCR-based test (Test takes 1 hr 45 min) Sputum liquefaction and inactivation with sample reagent 2:1, transfer 2ml mix into test cartridge, cartridge inserted into MTB-RIF test platform. Sample is filtered and washed, ultrasonic lysis of cells to release DNA, DNA mixes with dry PCR reagents, amplification of DNA.

Answer 216

Key to treatment: long-term treatment (6 mos. to 2 yrs) with a combination of antibiotics to prevent resistance  Key problems: patient compliance; emergence of multi-drug-resistant (MDR) strains; directly observed treatment - forced treatment  First-Line Drugs  Isoniazid, Ethambutol, Rifampin, Pyranizamide, Streptomycin Isoniazid: cell wall synthesis (mycolic acid) Ethambutol: cell wall synthesis; specific to Mycobacteria Pyrazinamide: fatty acid synthesis Streptomycin: protein synthesis (acts only on extra-cellular bacteria)  Second-Line Drugs  para-Aminosalicylic acid, Ethionamide, Cycloserine, Fluoroquinolones, Kanamycin ``` para-Aminosalicylic acid: folate synthesis Ethionamide: protein synthesis Cycloserine: cell wall synthesis Fluoroquinolones: DNA replication Kanamycin: protein synthesis ```

Answer 217

MDR TB caused by bacteria resistant to best TB drugs (at least the first line drugs) e.g isoniazid in combination with rifampin. Often resistant to additional drugs.  XDR TB caused by organisms resistant to isoniazid and rifampin, plus fluoroquinolones and ≥1 of the 3 injectable second-line drugs

Answer 218

Public Health Measures - Infection control, PPD tests, X-rays, case registries, contact tracing, “Directly Observed Treatment” (DOT) etc. - National TB center at NJMS  Prophylaxis Isoniazid given to persons suspected to be infected  BCG Vaccination Bacillus Calmette-Guerin Widespread worldwide Not routine in the US Note: cattle strain - BCG vaccination is given worldwide but not in US. Believe to confer immunity in children but not maintained into adulthood. - Giving BCG Vaccination we cannot use the PPD test thus we lose a valuable diagnostic test.

Answer 219

Pt with limb deformities and Leprae bell. Patients had to carry bell to announce their presence in public areas. due to the stigma name was changed to Hansen’s Disease.

Answer 220

 Acid-fast bacillus, very slow-growing, obligate intracellular parasite, grown in armadillos, or in footpads of mice; no artificial growth medium known  Epidemiology  Not highly infectious—requires prolonged person-person contact (reservoir: humans)  Pathogenesis  Infects macrophages, Schwann cells; invades peripheral sensory nerves (patchy anesthesia)  Immunity CMI, with DTH response to lepromin (similar to tuberculin)

Answer 221

Tuberculoid Form - may stay or progress to Lepromatous form  Macules (flat areas with hairless centers). Indolent (causing little or no pain), usually non-contagious; CMI active  Lepromatous Form  CMI defective, massive growth of M. leprae, “leonine” appearance, extensive skin lesions and deformation

Answer 222

``` Diagnosis Acid-fast bacilli in skin scrapings Serological tests, clinical findings  Sociological issues—stigma & patient sensitivity  Treatment - Dapsone + Rifampin very effective - Clofazimine added for lepromatous disease to prevent resistant forms ```

Answer 223

``` Tuberculoid- NON-PROGRESSING DISEASE Macular skin lesions Few bacilli in lesions CD4 Th cells IL-2, IFN gamma, IL-12 promote healing ``` ``` Lepromatous - PROGRESSIVE DISEASE Nodular skin lesions Abundant bacilli in lesions CD 8 suppressor T cells IL-4 and IL-10 suppress healing ```

Answer 224

“…a disease of the poorest of the poor…” | -WHO

Answer 225

In Southern US states population different strain of M. Leprae (compared to the one most common to produce infection globally) that also found in the natural armadillo population. Perhaps handling/consuming armadillos led to this initiation of different strain in human population of Southern US states.

Answer 226

“Atypical” Mycobacteria - mostly affect immunocompromised individuals  Soil and environmental bacteria All are acid-fast staining Cause granulomatous diseases Resistant to treatment  M. kansasii is photo-chromogenic and produces a slow TB-like disease  M. avium-Intracellulare Complex (MAC; non-chromogenic) causes TB-like disease in AIDS patients, MAC causes systemic infection as well Atypical Mycobacteria are also known as MOTT for “Mycobacteria Other Than Tuberculosis” Note: photo-chromogenic when grown in a slant and incubated in light will exhibit a yellow pigment.

Answer 227

Gram +ve anaerobic bacilli, branched cells; NOT acid-fast  Commensals (discussed under “normal flora”); opportunistic pathogens  “Sulfur granule” (clumped bacterial colonies; no sulfur!) is diagnostic  Actinomycosis is an inflammation of mucosal surfaces eventually opening through skin; typically cervicofacial  Associated with poor dental hygiene, tooth extraction  Diagnosis: nature of lesion, slow progression, mucosal damage history, “sulfur granules”, culture  Treatment: Penicillin G Note: Sulfur granule : clumped colonies of the bacteria (no sulfur actually present)

Answer 228

Gm +ve, branched, aerobic, weakly acid-fast, soil bacteria  Opportunistic pathogen  Nocardiosis (Two forms)  Pulmonary (N. asteroides; acute broncho-pneumonia with dyspnea, cough, sputum; mainly in immune-compromised individuals)  Cutaneous (N. brasiliensis; pustules and lesions with sinuses at injured or exposed sites; e.g., “mycetoma”; “Madura Foot”)  Diagnosis: Gm +ve branched cells in sputum or aspirates  Treatment: sulfonamides Note: Pulmonary- pulmonary disease similar to TB Cutaneous- surface injury gives room for the opportunistic bacteria

Answer 229

1. Metabolic characteristics of Mycobacteria 2. Lack of bactericidal activity of some drugs 3. Toxicity which may preclude the use of or necessitate less than optimal doses 4. Inadequacy of host defenses 5. Development of resistant strains

Answer 230

``` Isoniazid Rifampin Pyrazinamide Ethambutol Streptomycin ``` Note: all can be given oral EXCEPT STREPTOMYCIN -IV

Answer 231

Intensive phase with e.g. four primary drugs for about 2 months and then the continuation phase with about two drugs (of the intensive phase) for about 4 more months

Answer 232

``` p-aminosalicylic acid cycloserine ethionamide viomycin capreomycin kanamycin ciprofloxacin clofazamine rifabutin clarithromycin azithromycin ```

Answer 233

Hetero cyclic ring with N para carboxyl amino group

Answer 234

* Interferes with M. tuberculosiscell wall synthesis by inhibiting mycolicacid synthesis * Bactericidal to growing cultures •Bactericidal activity requires 2 steps: 1. Activation of INH 2. Complex of activated INH with NADH * Spectrum is limited primarily to M. tuberculosis (microbe does the activating) * KatG (is the gene that expresses the peroxidase enzyme) is a catalase–peroxidase enzyme * Isonicotinyl-NADH complex* is formed in the active site of an enoyl acyl carrier protein reductase (ACP reductase) * ACP reductase reduces the double bond at position 2 of a growing fatty acid chain linked to ACP (≥ 16 carbons) Note: Isoniazid is a prodrug and must be activated by KatG (a bacterial catalase-peroxidase enzyme that in mycobacterium tuberculosis). KatG couples the isonicotinic acyl with NADH to form isonicotinic acyl-NADH complex. Note: This complex* binds tightly to InhA (the enoyl-acyl carrier protein reductase), thereby blocking the natural enoyl-AcpM substrate and the action of fatty acid synthase. This process inhibits the synthesis of mycolic acid, required for the mycobacterial cell wall.

Answer 235

Chromosomal mutations * Mutations in KatG catalase-peroxidase resulting in lowered affinity for isoniazid * Deletion of KatG * Mutations in InhA which lower affinity for NADH and result in decreased ability to covalently bond INH with NADH

Answer 236

Absorption–Distribution: * Peak level of 3-5 μg/mL 1–2 hrs after oral administration * Vd = TBW; penetrates cells; enters pleural and ascitic fluid and caseous material; enters CSF and crosses the placenta Excretion: •75 to 95% of dose is excreted by the kidneys within 24 hrs, mostly as metabolites Vd = Volume of distribution

Answer 237

``` R = rapid acetylators (autosomal dominant) S = slow acetylators ``` INH ---- *N-acetyl transferase + Acetyl CoA *--->Acetyl isoniazid ---- Hydrolysis --->isonicotinic acid (not active) + Monoacetylhydrazine (is reactive and thought to cause hepatotoxicity) Or INH -----> Hydrazone (benign) ** = conjugation type rxn Note: metabolism does not occur in hepatocytes

Answer 238

R = rapid acetylators (autosomal dominant)

Answer 239

1.Exhibit greater risk for isoniazid toxicity •Peripheral neuropathy and hepatotoxicity. 2. Exhibit more drug interactions 3. More rapid anti-mycobacterial response Clinically not significant: not Much of a difference in the overall rate of clearing and the relatively low incidence of the side effects. Thus we don't sequence pt.s to determine what kind of acetylator they are.

Answer 240

Hypersensitivity • Various rashes (2%) ``` Peripheral Neuropathy •increased excretion of pyridoxine •axon terminal degeneration •supplement with B6 to reduce risk •slow acetylators are at more risk ``` CNS toxicity •dizziness, ataxia •convulsions (individuals with seizure disorders) - Increased of hepatotoxicity esp with patients who already have a deterioration of hepatic fxn e.g. drug users, alcoholics, etc. Note: INH complexes with pyridoxine and induces its secretion. Decrease of Vit. B6 we get peripheral neuropathy.

Answer 241

Increased incidence with age 49 2.3%

Answer 242

Isoniazid Drug Interactions •Phenytoin •Disulfiram •Oral anticoagulants Drug-induced Lupus Erythmatosus (does not occur with INH) •Procainamide •Hydralazine

Answer 243

TB and can be used for meningicoccal carrier state. A terminal end methyl undergoes enterohepatic metabolism macrocyclic antibiotic MW = 823 highly lipid soluble

Answer 244

Inhibits DNA dependent RNA polymerase leading to suppression of chain initiation * Selective toxicity is conferred by the poor affinity for the mammalian enzyme; thus we can use small doses to affect microbe and not humans. * Resistance occurs when binding site on polymerase is altered so that rifampin cannot bind to the ß-subunit (chromosomal mutation)

Answer 245

* Effective against Mycobacterium tuberculosisas well as some atypical strains * Prophylaxis of Meningococcal and H. influenzaeinfections

Answer 246

* Well absorbed orally; absorption delayed by p-aminosalicylic acid * Well distributed; effective concentrations in the CNS; Vd = 160% of body weight * Undergoes enterohepatic circulation; de-acetylated form is not absorbed from the intestine * Primarily biliary excretion * Plasma half-life is 2–5 hrs and may by prolonged in hepatic insufficiency Note: p-aminosalicylic acid not really used anymore. And Rifampin can cross fatty tissue and enter cells well.

Answer 247

1. Overall incidence is about 4% 2. Most common are GI complaints (1–2%) 3. Mild, self-limiting rash (0.8%) 4. Asymptomatic elevation of liver enzymes (SGOT, pyruvate kinase) 5. Hepatitis with jaundice ( 1200 mg/day) a. Allergy: drug fever, flu-like symptoms in 20% of patients b. Eosinophilia, tubulointerstitialnephritis c. Rarely thrombocytopenia, hemolytic anemia 7. Colors all bodily excretions and secretions orange-red - Pt.s should be advised of this. Tears, sweat, saliva, urine. etc.

Answer 248

Drug Interactions Rifampin is an inducer of microsomal MFO. Decreases the effectiveness of: oral contraceptives, methadone (prevent withdrawal symptoms), oral anticoagulants, quinidine, digitoxin, ketoconazole, glucocorticoids propranolol, oral hypoglycemics, metoprolol Note: Many drugs are metabolized by CP450 - a mixed function oxidase. Rifampin induces the production of more CP450 enzymes leading to a decrease in the effectiveness of drugs that undergo hepatometabolism with CP450.

Answer 249

All of the TB drugs we do not give as a monotherapy because with a very short period of time a resistant TB will be selected. Prophylaxis is the only time we use mono therapy for e.g. INH for close contact members of a confirmed TB infected person Bactericidal Orally active Well distributed Hepatotoxic (used to be very prevalent mostly due to because was given at such a high dose but now given with rifampin and now less prevalent) The microbe removes the amine of Pyrazinamide which becomes the active produce Pyrazionic acid. Pyrazinoic acid (appears in our blood, gets hydroxylated and excreted like this) produced in mycobacterium; PYRAZINOIC ACID IS THE ACTIVE BACTERICIDAL PRODUCT Pyrazinoic acid appears in our blood and gets hydroxylated (5-hydroxy pyrazinoic acid). Metabolite (which is what gets excreted) interferes with uric acid excretion thus must monitor patients who suffer from gout and assess pain.

Answer 250

Ethambutol (orally active) •Bacteriostatic •Only effective against Mycobacteria •Inhibits arabinosyl transferase which is necessary for polymerization of arabinogalactan cell wall components

Answer 251

* Well absorbed orally * Concentrated in red blood cells: RBC/plasma concentration ratio is 2:1 * Excreted in urine; 50% as parent compound * Half-life is 8 hrs

Answer 252

1. Optic neuritis–diminished visual acuity; inability to perceive green; dose dependent; unilateral 2. Allergic reactions are rare: dermatitis, arthralgia 3. Hyperuricemia Note: Optic neuritis - evaluate their vision and do each eyes separately. Difficult when dealing with a child bc of their knowledge of Snell's chart.

Answer 253

Informational

Answer 254

Diagnosis A. Signs and symptoms 1. > 2 years old – high fever and headache (90%), nuchal rigidity (60%), vomiting, confusion, sleepiness, seizures, sensitivity to light (coma and death within hours) 2. infants – classic symptoms often absent or difficult to detect (slow, inactive, irritable, feeding poorly, vomiting) B. Direct Gram stain of CSF often reveals bacteria. Reliable latex bead agglutination assays available for detecting bacterial antigens in CSF. Bacteria must be cultured for positive diagnosis.

Answer 255

Bacteria: Cell type and count - PMNs, 1-5K ; Glucose - Reduced ; Protein- 100 to 2,000 mg/dL ; Lactate- elevated Viruses: Cell type and count- Lymphocytes, 50-500 ; Glucose - Normal ; Protein- 10 to 100 mg/dL ; Lactate- Normal Yeast and Tb = Cell type is mixed and count 10-100 ; Glucose - Reduced ; Protein- 100-500 ; Lactate- elevated Note: with inflammation it allows for WBCs to get in. Normal CSF will have 0-10 Cell counts of WBCs. Also the grand number of PMNs accounts for the puss in the brain. Cell count: per microliter.

Answer 256

Informational

Answer 257

1. Antiphagocytic capsule | 2. Serum resistance

Answer 258

A. Ecology - normal flora of nasopharynx of humans (5-10%). B. Infection spreads from nasopharynx  blood  meninges C. Causative Agent - gram negative diplococci D. Encapsulated, antigenic structure based on capsule 1. A, B, C, D, X, Y, Z, 29E, W135 (capsular polysaccharides) 2. A, B, C, Y and W135 most often associated with disease E. Virulence factors: 1. Capsule – inhibits phagocytosis 2. Serum resistance 3. IgA protease – adhesion 4. Pili – adhesion 5. LOS – lipooligosaccharides (~ LPS), but highly endotoxic and often sialylated

Answer 259

Pathogenesis - highly contagious disease with significant mortality rate in a closed population. 1. Meningococcemia and/or meningitis can cause fulminate with death in a few hours in a previously healthy individual. Meningococcemia can be associated with petechial rash or purpura (skin hemorrhage) 2. Waterhouse-Friderichsen Syndrome (massive hemorrhage and adrenal necrosis) 3. Sequelae: hearing loss, mental retardation G. Lab Diagnosis 1. Gram stain of CSF 2. CSF and blood culture a. Chocolate agar - 5% CO2 i. Small, colorless, nonhemolytic, oxidase positive colonies ii. Fermentation (glucose, maltose positive) iii. Agglutination test with specific antisera b. Thayer-Martin or GC-Lect agar for isolation from nasopharyngeal carriers 3. Latex agglutination to detect antigens in CSF--This test is not performed if glucose, protein and cell count are in normal range

Answer 260

Epidemiology (respiratory secretions) 1. Sporadic cases 2. Epidemics a. Associated with rise in carrier state (5-10% to 70-80%) b. Prevalent in closed groups (military barracks, college dorms) c. Meningitis Belt in Sub-Saharan Africa (dry seasons) 3. Terminal complement component (C5-C9) deficiency elevates incidence of infection 4. Neonates resistant (maternal antibody protects), but young children are at risk because they lack the protective antibody I. Treatment - Penicillin I.V. J. Prevention 1. Chemoprophylaxis of carriers: Rifampin, Ciprofloxacin 2. Vaccination with quadravalent vaccine (Gp A, C, Y, W135) B is not immunogenic. Used by military and now recommended in colleges. New Jersey now requires all college freshmen to be vaccinated.

Answer 261

A. Ecology – Normal flora of the nasopharynx (unencapsulated 35-90% of population); humans only; most frequent cause of meningitis in children under 4 years of age; peak incidence is 6 months. B. The Organism 1. Gram negative, cocco-bacillary, encapsulated, frequently pleomorphic C. Antigenic Structure 1. 6 Types of polysaccharide capsule: a to f (type b associated with 90% disease) 2. Nontypables may be seen, but rarely cause disease D. Pathogenesis 1. URI (upper respiratory infection), sinusitis, pneumonia and otitis media (second to S. pneumoniae), septicemia, meningitis, conjunctivitis, epiglotitis 2. Sequelae can occur after meningitis (similar to N. meningitides)

Answer 262

Laboratory Diagnosis 1. Gram stain of CSF 2. CSF and Blood Culture - chocolate agar, 5% CO2 Requires X factor (tetrapyrrol compounds - hemin - for cytochrome synthesis) and V factor (NAD for respiration) 3. Latex agglutination to detect capsular antigen in CSF Epidemiology 1. Spread by droplet - may also cause pharyngitis, sinusitis and otitis media 2. Sporadic, starting to become more common in adults (especially pneumonia). Meningitis in children in US has become uncommon because of vaccination. G. Treatment 1. Ceftriaxone – adults; cefotaxime – children; 2. Chloramphenicol H. Prevention 1. Chemoprophylaxis – rifampin to close contacts of index case (i.e. day care center) 2. PRP capsular conjugate vaccine (Hib vaccine) for children two months and older

Answer 263

A. Ecology – humans; normal flora of nasopharynx (5-70%) B. The Organism 1. Gram positive diplococci, lancet shaped 2. -Hemolytic on blood agar 3. Capsule - prevents phagocytosis C. Antigenic Structure 1. 85 Polysaccharide capsule types (23 types responsible for 85% of disease) 2. Nontypables of low or no virulence D. Pathogenesis 1. Loss of natural resistance 2. Lobar pneumonia, otitis media, septicemia, meningitis (most common cause in individuals over 30 years of age 3. Sequelae similar to N. meningitidis

Answer 264

Laboratory Diagnosis 1. Gram stain of CSF 2. CSF and Blood culture 3. Small, grayish, -hemolytic colonies 4. Optochin-sensitive and bile soluble 5. Oxacillin disc screen for relative or complete resistance to penicillin Epidemiology 1. Respiratory secretions 2. Peak winter and spring 3. Most common cause in adults > 30 year of age, often associated with head trauma 4. In the U.S., S. pneumoniae is becoming more common cause of meningitis in children than H. influenzae due to Hib vaccine 5. At risk are: asplenic individuals and individuals with sickle cell anemia (which damages the spleen) and humoral immunity, alcoholics G. Treatment 1. Penicillin - Resistant strains in Africa, Europe and appearing in US. 2. Ceftriaxione; 3. Vancomycin H. Prevention: Polyvalent vaccine (Pneumovax) and congugate vaccine (Prevnar) 1. Polyvalent vaccine – compromised host and individuals > 65 2. Conjugate vaccine – children

Answer 265

1. Normal flora: GU and lower GI (25-40% of females) 2. Early onset - first five days of life a. Pregnancy problems b. 25-40% of females have this organism as part of the normal vaginal flora 3. Late onset - 7 days to 3 months a. Preobstetric problems 4. Diagnosis - discussed under gram positive cocci lecture 5. Treatment – Penicillin during labor for women at risk or GBS + at 33-36 weeks.

Answer 266

B. E. coli (80% of meningitis caused by E. coli is due to a single strain, K1). C. Listeria monocytogenes 1. Gram positive rod a. Grows at 4oC b. Faintly -hemolytic c. Tumbling motility at room temperature, not at 37oC 2. Ecology - found in many animals 3. Intrauterine infection a. Early onset syndrome - intrauterine sepsis and fetal death prior to/after delivery b. Late onset syndrome - no obstetric complications 4. Meningitis in the neonate and the immunosuppressed 5. Treatment -Penicillin 6. Epidemiology – unknown, recent cases in California associated with eating unpasteurized goat cheese D. Staphylococcus aureus, or Enterococci

Answer 267

``` A. Coagulase negative staphylococci B. Staphylococcus aureus C. Gram negative rods D. Enterococci E. Candida F. Corynebacteria ```

Answer 268

``` A. Mycobacteria tuberculosis B. Cryptococcus neoformans C. Coccidioides immitis D. Histoplasma capsulatum E. Blastomyces dermatitidis F. Candida albicans G. Borrelia burgdorferi H. Cysticercosis (T. solium) ```

Answer 269

Bacterial is more sever with a rapid increase of high risk patient and mortality of 35-40% Viral is less sever

Answer 270

``` Individuals > 2 yrs • High fever (103-104) • Headache (excruciating pain) • Nuchal rigidity • Other: vomiting, confusion, sleepiness, seizures, sensitivity to light • Coma and death in hours ``` Infants • Classic symptoms absent or difficult to detect (slow, inactive, irritable, feeding poorly, vomiting) Note: If someone doesn't exhibit these signs doesn't not allow to rule out meningitis. Symptoms hold true about 65% of the time.

Answer 271

• Examination of CSF o Direct Gram stain - no stain then viral; stain ---> bacterial or fungal o WBC type & number o Glucose concentration compared to blood o Protein levels o Latex bead agglutination • Confirmation: lab culture of CSF & blood (takes a couple of days for the culture) Note: Bacterial glucose will be low because of glycolysis

Answer 272

``` Bacterial - elevated PMNs and proteins -  glucose and lactate Viral - elevated lymphocytes - normal glucose and lactate ```

Answer 273

Location: Location, location, location Adults - nasopharynx and into blood Newborns - usually from the urogenital tract of mother ``` Newborn/Neonates (less than on month): Streptococcus agalactiae (45%) Listeria monocytogenes (2-10%) Haemophilus influenza 0-3% Streptococcus pneumoniae 0-5% Neisseria meningitides ```

Answer 274

N. meningitidis - adolescents and young adults H. influenzae - most common in young children (where vaccine Hib is not used) S. pneumoniae - most common in young children (where Hib vaccine used) and in adults Hib vaccine so effective because H. influenza type B was the most common serotype to cause meningitis.

Answer 275

N. meningitidis, H. influenzae, S. pneumonias Common Properties 1. Anti-phagocytic capsule 2. Serum resistance - travel via blood is the way bacteria get to CNS thus being serum resistant is bad for host. Capsule can block opsonization (phagocytosis) by both C3b and IgG (if capsule is not the Ag)!! Note: Gram + are more serum resistant because do not have LPS which induces opsonization.

Answer 276

* Normal flora: Nasopharynx (5-10% carriers) * Nasopharynx --> blood--> meninges * Gram -, diplococcus • Encapsulated - > 15 distinct Ag structure, based on capsule o A, B, C, Y, W135 associate with disease o 60-90% adults protective Ab to more than 1 type

Answer 277

* Capsule – inhibits phagocytosis * IgA protease – adhesion * Pili – adhesion * LOS – lipooligosaccharide (~LPS), (highly endotoxic & often sialylated) Simpler sugars in extracellular space- missing O antigen and has a lower MW O chain.

Answer 278

Meningococcemia, meningitis - Petechial rash & Purpura (skin hemorrhage) - Waterhouse-Friderichsen syndrome (massive hemorrhage & necrosis of adrenals) • Sequelae: Hearing loss, mental retardation Note: Petechia is almost always related to bacteremia. Purpura is massive skin hemorrhaging.

Answer 279

• Gram stain of CSF: Gram (-) diplococcus • CSF & blood: chocolate agar, 5% C02 • Small colonies, oxidase positive • Fermentation test: glucose & maltose • Agglutination test (CSF & culture) Diagnosis

Answer 280

•Transmission: Respiratory secretions * Sporadic cases - occurring at irregular intervals or only in a few places; scattered or isolated. * Epidemics - Closed population (military, dorms) - Rise in carrier state (5-10% increased to  70-80%) •Terminal complement component (C5-C9) - deficiency elevates incidence of infection •Neonates resistant (maternal Ab), but young children at risk (lack protective Ab)

Answer 281

• Treatment – Antibiotic • Prevention o Chemoprophylaxis of carriers: rifampin, ciprofloxacin o Vaccination: Quadravalent vaccine (A, C, Y, W135) used by military & recommended in college (Group B is not immunogenic) Note: We now have a pentavalent vaccine for all 5 groups.

Answer 282

• Normal flora: Nasopharynx (unencapsulated 35-90%) • Gram - , encapsulated, cocci-bacillus • Antigenic structure o 6 Capsule types (a-f); virulent = type b (90%) o Non-typables rarely cause disease Vaccine for capsule type B is very effective

Answer 283

• Septicemia, meningitis, conjunctivitis, epiglottitis (croup) • Pneumonia & otitis media (2nd most common to S. pneumonias) • Sequelae: ~ N. meningitides (i.e. Hearing loss, mental retardation)

Answer 284

• Gram stain CSF • CSF & blood culture: o Chocolate agar, 5% C02 o Large, flat, colorless – grey colonies o Require factors X (hemin) & V (NAD, NADP) • Latex agglutination -patient's CSF, serum or urine with the coated latex particles (coated with Ag) and observe for agglutination. Agglutination/clumping of the beads in any of the dilutions is considered a positive result, confirming that the patient has produced the pathogen-specific antibody.

Answer 285

* Transmission: respiratory secretions * Sporadic – children * Hib once account for 98% H. influenzae meningitis in children

Answer 286

• Treatment o Antibiotic • Prevention o Chemoprophylaxis: rifampin to close contacts (i.e. day care center) of index case o Conjugate vaccine - children older than 2 months - conjugated with protein carrier Note: with the introduction of Hib vaccine in 1992 the incidence of total serious Hib decreased but their was a slight surge with unvaccinated children from 1997-2003. This was due to the now discredited claim of vaccine assoc. to autism. In 2003 the catch-up campaign was initiated to protect a generation of children, born between 1997 and 2003, who are unvaccinated or only partially vaccinated against measles.

Answer 287

* Normal flora: nasopharynx (5-70%) * Gram +, lancet-shaped, diplococci * alpha Hemolytic • Antigenic structure o 85 capsule types (23 85% disease) o Non-typables of low or no virulence Note: recall this is most frequent cause of otitis media

Answer 288

* Lobar pneumonia, otitis media * Meningitis - most common cause in adults > 30 yrs * Sequelae: ~ N. meningitides (i.e. Hearing loss, mental retardation)

Answer 289

* Gram stain CSF (Gram +) * CSF and blood culture - small, greyish, a-hemolytic colonies - Bile soluble (activates autolysins) - Optochin sensitive - Oxacillin disc screen (penicillin resistance) : is a narrow-spectrum beta-lactam antibiotic of the penicillin class Note: if they come in with otitis media penicillin may be appropriate but if meningitis is clinically presented hit 'em with the big guns.

Answer 290

Transmission: respiratory secretions * Winter and spring * Often associated with head trauma * In US, S. pneumoniae > H. influenzae as cause of meningitis (Hib vaccine) * At risk: asplenic, sickle cell anemia (sickle cell anemia damages spleen), defects in humoral immunity, alcoholism

Answer 291

• Treatment - Penicillin (except resistant strains) • Prophylaxis - Polyvalent vaccine (Pneumovax) – at risk, > 65 - Congugate vaccine (Prevnar 13 (capsules)) in 2000 –

Answer 292

Streptococcus agalactiae (GBS) "Group B streptococcus" catalase-, Gm +, beta hemolytic • Normal flora: GU & lower GI (25 - 40% of females) • Early-onset (0-5 days) infection (most) • Late-onset (1 - 12 wks) infection • 1-3 cases/1000 births; 30 - 60% mortality Note: largest % of total cases is the early onset Note: Most is that they were exposed during birth or the less common that one of the handlers exposure.

Answer 293

Streptococcus agalactiae (GBS) "Group B streptococcus" 50/50 non colonized newborn: colonized newborn Of the colonized newborn 98% asymptomatic and 2% Early-onset sepsis, pneumonia, meningitis

Answer 294

• Diagnosis - Group B agglut’n • Treatment – Penicillin • Prophylaxis – Penicillin (before and during labor of mothers at risk or GBS positive in vagina or rectum)

Answer 295

* Gram (+) bacillus * Grows unusually at 4oC * * Tumbling motility at 21oC** (not 37oC) * Early & late onset infection * Important cause in immunosuppressed (also in the elderly) * Treatment - penicillin Note: Almost any bacteria will not grow at 4oC. E.g refrigerated soft cheese (non pasteurized) consumption can be an issue Note: Motility at room temperature 12oC is an easy Diagnostic

Answer 296

• Strain K1 - 80% neonatal septicemia & meningitis Staphylococcus aureus Enterococcus **** Not on EXAM

Answer 297

* Coagulase-negative Staphylococcus * Staphylococcus aureus * Gram-negative rods * Enterococcus * Candida (Fungi) * Corynebacterium Note: Other pathogens found in normal flora of nasopharynx of adults children and exposure from UG/GI in neonates may get into bloodstream and into CNS

Answer 298

* Mycobacteria tuberculosis * Cryptococcus neoformans (AIDS patients) * Coccidiodies immitis * Histoplama capsulatum * Blastomyces dermatitidis * Candida albicans * Borrelia burgdorferi * Cysticercosis (T. sodium) Note: Much more difficult to diagnose and if given the opportunity may cause meningitis. Steroid injections into CSF (poor quality control) led to contraction of a type of fungus ---> meningitis. Much more difficult to treat parasites and fungi is much more difficult because they are more like human cells.