Bacteria Cont, Cell-Wall Antimicrobials (Week 3)

Question 1

Streptococcus pneumoniae

Answer 1

Pneumococcus

Gram +, encapsulated, lancet shaped, diplococci, facultative anaerobe, alpha-hemolytic, naturally competent

Most common cause of community-acquired pneumonia, bacterial meningitis and meningitis in adults

Question 2

What allows us to defend against encapsulated bacteria?

Answer 2

ANTIBODIES!

Complement cannot opsonize/phagocytize/membrane attack complex encapsulated bacteria

Question 3

Pneumococcal pneumonia

Answer 3

From Streptococcus pneumoniae

Purulent exudate-filled alveoli –> bronchopneumonia, lobar pneumonia, cough

Immunity by antibodies because it is encapsulated (infection or vaccine)

Question 4

Neisseria meningitidis

Answer 4

Gram -, diplococci, encapsulated

Nasopharyngeal carriage and transmitted in respiratory droplets

Virulence factors: LOS endotoxin, secretes IgA1 protease, pili, capsule

Can do transcytosis (bind apical side of cell, transit through cell and exit basolateral side of cell)

Diseases: meningitis (CNS diesase), meningococcemia (septicemia), both together

Question 6

Drug classes that inhibit cell wall synthesis

Answer 6

Beta-lactam antibiotics: penicillins, cephalosporins; contain 4-membered beta-lactam ring structure

Vancomycin

Bacitracin

Bactericidal; only work on actively proliferating microorganisms

Question 7

Beta lactam antibiotics

Answer 7

Inhibit transpeptidase enzmes that cross-link peptidoglycan matrix

Ex: Penicillins, cephalosporins

Contain 4-membered beta-lactam ring structure

Bactericidal

Effective against mixture of gram + and gram - bacteria

If bacteria contains beta-lactamase (ie penicillinase or cephalosporinase) then will be resistant to beta-lactam drugs

Question 8

Penicillins

Answer 8

Interfere with one of final steps in bacterial cell wall synthesis and cause cell lysis

Can cause hypersensitivity

Question 9

Transpeptidase

Answer 9

Bacterial enzyme that cross-links peptidoglycan matrix to form cell wall

Located in cytoplasmic membrane

AKA penicillin binding proteins (PBPs)

Question 10

Bordetella pertussis

Answer 10

Gram - coccobacillus (small)

Obligate aerobe

NOT part of normal flora, but live in healthy ciliated epithelial cells in infected people

Disease: Pertussis (whooping cough)

Transmission: respiratory droplets, highly communicable

Question 11

Clinical features of pertussis (whooping cough)

Answer 11

Incubation period: 7-14 days

Catarrhal phase: 7 days; mild cold-like symptoms

Paroxysmal phase: 1-4 weeks or longer; severe forceful spasmodic coughing followed by inspiratory gasp (whoop), lymphocytosis

Convalescent phase: several weeks; paroxysms less frequent/severe, gradual recovery

Question 12

In vaccinated populations, where is the reservoir of B. pertussis?

Answer 12

In adolescents and adults, who may be asymptomatic but can give B. pertussis to infants

Note: most cases occur in infants before the vaccine has given immunity

Question 13

Toxins secreted by B pertussis

Answer 13

1) Adenylate cyclase toxin: binds receptors on neutrophils, CDs, monocytes, is internalized, is activated by calmodulin to turn ATP to cAMP which inhibit the phagocytic cell form phagocytizing (disrupt chemotaxis, phagocytosis, killing bacteria)
2) Pertussis toxin (Ptx): A/B toxin takes ADP portion of NAD and links it to G alpha protein to inhibit its activity, but this G protein is itself inhibitory to adenylate cyclase in the host cell so this causes increase in cAMP in the host cell
3) Tracheal cytotoxin: is a fragment of bacterial peptidoglycan cell wall that stops cilia from beating and kills ciliated cells (this same toxin used by gonococcus)

Question 14

Haemophilus influenzae

Answer 14

Gram - coccobacillus (small)

Requires hemin (X factor) and NAD (V factor)

Grown on chocolate agar

Strains a-f are encapsulated and nontypeable are nonencapsulated

Diseases: otitis media in kids, pneumonia, epiglottitis, meningitis

Question 15

Which pathogens have conjugate vaccines?

Answer 15

Streptococcus pneumoniae

Neiserria meningitis

H. influenza

Note: all encapsulated (duh)

Question 16

Trimethoprim sulfonamide (TMP/SMX)

Answer 16

Widely active against Gram +/-

Used to be used for UTIs but no longer because E coli are more resistant

Tx CA-MRSA, Pneumocystis jiroveci pneumonia

NOT to tx Group A streap or enterococci (intrinsically resistant)

AKA Bactrim

Question 17

Important properties of sulfonamides

Answer 17

Highly protein bound

Undergo hepatic metabolism

Metabolite excreted by urine (may form crystals or stones in urinary tract)

Many possible toxicities (SJS)

Question 18

Drug interaction of sulfonamide and phenytoin

Answer 18

Sulfonamide produces phenytoin toxicity (too much phenytoin) because sulfa binds albumin and displaces phenytoin from albumin

Question 19

How do bacteria become resistant to sulfonamides?

Answer 19

1) Overproduce PABA (increase concentration of substrate so even though sulfa there to inhibit, reaction still proceeds)
2) Mutations in DHFR so that trimethoprim can’t bind/inhibit it

Question 20

Trimethoprim

Answer 20

Toxicities: nausea and vomiting, hematopoetic problems, interferes with Na/K exchange in kidney (hyperkalemia)

Question 21

Combination sulfa drugs

Answer 21

Pyrimethamine-sulfadoxine (Fansidar) used to treat malaria

Pyrimethamine-sulfadiazine used to treat toxoplasmosis

Note: sulfa drugs almost never prescribed alone

Question 22

Use of sulfonamides for other things

Answer 22

Use 1% silver sulfadiazine cream for prophylaxis against infection

Use sodium sulfacetamide drops for conjunctivitis

Question 23

Where do beta-lactams act?

Answer 23

Act on cell wall

If acting on gram - then must get through porins in outer membrane to act in periplasmic space

Note: mycobacteria have complex cell wall (or NO cell wall??) and beta-lactams usually don’t work against them

Question 24

Three groups of cell wall synthesis inhibitors

Answer 24

Beta-lactams

Glycopetides

Inhibitor of peptidoglycan precursor transport (Bacitracin, only used topically)

Question 25

Resistance to beta-lactams and our response

Answer 25

Degradation by beta-lactamases (all S. aureus is resistant because of this), but we combat this by using beta-lactamase inhibitors

Decreased permeability through porins (outer membrane of Gram -), but we combat this by adding different “R” groups to make drugs better able to penetrate (add amino group)

Altered penicillin binding proteins/transpeptidases (MRSA), but all we can do to combat this is to use another type of drug :(

Question 26

Beta-lactamase inhibitors

Answer 26

Since bacteria make beta-lactamase to avoid being killed by beta-lactams (penicillins), we created beta-lactamase inhibitors! Ex: **clavulanate**, **sulbactam**, **tazobactam** Note: amoxicillin + clavulanate = Augmentin

Question 27

Beta-lactam toxicity

Answer 27

**Hypersensitivity** Nausea, vomiting, diarrhea Neutropenia **GI disease** (C difficile) Neurotoxicity (seizure risk) Cation toxicity: Na and K disturbances when large doses of ticarcillin/carbenicillin given; Na load with piperacillin/tazobactam Interstitial nephritis (methicillin, others)

Question 28

Vibrio cholerae

Answer 28

**Curved** gram - rod (comma) **Single polar flagellum** for motility Secretory diarrhea (**"rice water diarrhea"**) Transmission is fecal-oral Cholera toxin is phage-encoded

Question 29

Campylobacter jejuni

Answer 29

**Curved**, spiral, gram - rods Reservoir in wild and domesticated animals Transmission: contaminated **food**, **water**, **milk** Common cause of diarrhea

Question 30

Helicobacter pylori

Answer 30

Most common cause of **gastritis** and **gastric** **ulcers** after NSAIDs Associated with cancer (gastric adenocarcinoma and gastric (**MALT**) **lymphoma**) **Motile** **Urease +**

Question 31

Cholera toxin

Answer 31

Secreted by **V. cholera** when in the lumen of gut A/B toxin "A" subunit enters cytoplasm, takes ADP ribose part of NAD and links it to G-alpha protein to lock it in active/GTP-bound state (links at GTPase portion so can no longer do GTP --\> GDP!) Continually active adenylate cyclase --\> huge amounts of cAMP --\> alteration of ion flux (Cl- and HCO3 secreted; Na and K uptake is blocked) --\> water follows salt to lumen of small intestine --\> **watery diarrhea** Note: genes for cholera toxin are on lysogenic bacteriophage

Question 32

Is cholera caused only by cholera toxin?

Answer 32

**No**, even when gene for cholera toxin (ctxAB) is deleted, still some people get sick Note: if gene for pilus (tcpA) is deleted, nobody gets sick because V cholerae can't colonize!

Question 33

Which cephalosporins can cause you to bleed more (increase PT time) and how?

Answer 33

**Cefotetan** and **Cefoperazone** Both have MTT side chain (R2) which interacts with vitamin K synthesis (remember, vit K needed for clotting) by **specifically affecting enzymes** in the vitamin K synthesis pathway Note: in general, any antimicrobial can decrease vitamin K metabolism by wiping out gut flora because that gut flora needed for vitamin K synthesis and this can lead to bleeding too; however Cefotetan and Cefoperazone cause MORE bleeding because they are specifically targeting vitamin K synthesis pathway

Question 34

What two types of antibiotics can be used synergistically to treat enterococcal infections?

Answer 34

**Beta-lactams** and **aminoglycosides** (gentamycin) (Because beta-lactams might not be fully bactericidal alone)

Question 35

Salmonella

Answer 35

Gram - bacillus, motile, enterobacteriaceae Non-lactose fermenter, produces H2S Enteric (**typhoid**) fever: **S. typhi,** S. paratyphi **Nontyphoidal** enteritis: S. typhimurium, **S. enteriditis,** etc Pathogenesis: typhoidal strains get into **macrophages** and prevent phagosome from killing them; Type III secretion system uses SopE and SptP to turn on/off Ras-Cdc42 to polymerize **actin** to open/close cell membrane to infect cell

Question 36

Carrier state of salmonella

Answer 36

Some people infected with salmonella become chronic carriers and have S typhi in their **gallbladders** **"Typhoid Mary"** contaminated food to everyone she cooked for

Question 37

Shigella

Answer 37

Gram - bacilli, non-motile (shigella has no flagella) **S. dysenteriae**, S. flexneri, S. boydii, S. sonnei Pathogenesis: similar to **EIEC** because both **invade** intestinal epithelial cells and release **Shiga toxin** to cause cell destruction; **cell-to-cell spread** Clinical manifestations: dysentery, **bloody** **diarrhea**, complications (bacteremia, **HUS**)

Question 38

Shiga toxin

Answer 38

Cleaves 28S rRNA, **inhibits protein synthesis** Causes **cell destruction** (usually in GI tract/intestinal epithelial cells) to cause **bloody diarrhea**

Question 39

Listeria monocytogenes

Answer 39

Gram + rod, non-spore forming, **tumbling motility** (tail of actin filaments being polymerized/depolymerized) Virulence factors: **listeriolysin O** allows escape from phagolysosomes of macrophages (avoid intracellular killing); **invasins** (InlAB), **ActA** polymerizes actin Diseases: **pregnant women** during 3rd trimester, **immunocompromised**/elderly meningitis, **neonatal** **meningitis** Note: need **CD4 T cell response** to activate macrophages to kill L monocytogenes before it escapes and doesn't allow macrophage killing!

Question 40

Enterobacteriaceae

Answer 40

Gram - Some are normal flora that become opportunistic (**E. coli, Klebsiella, Proteus**) or acquire virulence factor (toxigenic E. coli) Some are always a pathogen (**Salmonella, shigella, yersinia**) Virulence factors in general: flagella (**H antigen**), capsule (**K or Vi antigen**), LPS, sequestration of growth factors, antimicrobial resistance

Question 41

Escherichia coli

Answer 41

Gram - bacillus (rod) **Lactose** fermenting, oxidase negative, reduces nitrates to nitrites Virulence factors: adhesins (**pili**), **exotoxins** (LT and ST, shiga-like toxin), **endotoxin** (lipid A of LPS) Diseases: **diarrhea**, **UTI**, **neonatal** **meningitis**, **neonatal pneumonia, sepsis** secondary to infection at other site

Question 42

Different types of E. coli infections

Answer 42

1) Enterotoxigenic E. coli (ETEC) 2) Enteropathogenic E. coli (EPEC) 3) Enteroinvasive E. coli (EIEC) 4) Enterohemorrhagic E. coli (EHEC) 5) Enteroaggregative E. coli (EAEC) **APITH**

Question 43

Enterotoxigenic E. coli (ETEC)

Answer 43

**Watery** (secretory) diarrhea (but milder than cholera) No histologic changes in bowel mucosa (no inflammatory response) **Traveler's diarrhea** (T for traveler's) **Heat labile** AB toxin increases cAMP to cause ion secretion (labile like the Air) **Heat stable** monomer toxin increases cGMP (stable like the Ground)

Question 44

Enteropathogenic E. coli (EPEC)

Answer 44

**Watery diarrhea**, fever, nausea and vomiting **Infant** diarrhea in developing countries; rare in adults E coli destroy/**flatten microvilli** to cause **malabsorption**, so would see histological changes (inflammation) **Type III secretion** injects intimin receptor to bind adhesin; get attachment/effacement lesions

Question 45

Enteroinvasive E. coli (EIEC)

Answer 45

Very similar to **Shigella** (main virulence factor encoded by plasmid shared by Shigella and E. coli = **shiga-like toxin**) Watery diarrhea may become a little **bloody**; **fever**, WBCs in intestinal wall and stool; dysentery in developing countries E. coli actually invades epithelial cells and host causes inflammation to get rid of bacteria

Question 46

Enterohemorrhagic E. coli (EHEC)

Answer 46

**Bloody** **diarrhea**, severe abdominal cramps (hemorrhagic colitis), usually no fever Hemolytic uremic syndrome (**HUS**) with anemia, thrombocytopenia, renal failure when have E. coli **0157:H7** (most common in US) Most common in developed countries (from contaminated meat, cheese, etc) Secrete **shiga-like toxin** (verotoxin) which destroys intestinal cells; get attachment/effacement lesions

Question 47

Enteroaggregative E. coli (EAEC)

Answer 47

Chronic **watery** diarrhea (**infants** in developing countries; AIDS pts) Bundle-forming fimbriae AAF-I and -II, no cytotoxin Not as common

Question 48

Shiga toxin

Answer 48

**Stx-1, Stx-2** Phage transduced AB toxin Gets into submucosa and capillaries to halt protein synthesis (inhibits 60S ribosome of host) Causes **destruction** of intestinal villus cells, A/E lesions **Hemolytic uremic syndrome** associated with **Stx-2** Shiga toxin secreted by **EHEC, EIEC**

Question 49

Klebsiella

Answer 49

Encapsulated with **thick capsule** (with O antigen) but **non-motile** (so no H antigen) Causes **sepsis**, **UTIs** and **pneumonia** (bloody sputum = **currant** **jelly**; **lobar** **pneumonia**) in **hospitalized** patients Increasing drug resistance is emerging (KPC carbapenemase producing strain is spreading)

Question 50

Proteus mirabilis

Answer 50

Motile, **urea**-**splitting** (will find alkaline/**high** **urine** **pH**), doesn't ferment lactose, oxidase negative Increased pH precipitates ammonium magnesuim phosphate, leading to **urinary stones** **Swarms**, forms confluence on agar plate Common cause of **UTIs** and nosocomial infections Note: also have Proteus vulgaris, similar?

Question 51

Nosocomial gram negative rods

Answer 51

Enterobacter Citrobacter Morganella Serratia These can cause nosocomial pneumonia, UTI, bloodstream infection, meningitis (after neurosurg procedure) Have increased antimicrobial resistance (extended spectrum beta lactamase production; inducible chromosomal resistance (initially appears susceptible but resistant strains emerge quickly))

Question 52

Pseudomonas aeuginosa

Answer 52

**Aerobic**, Gram - rod Lactose negative, oxidase positive, produces **green-blue pigment**, has **grape-like odor** Virulence factors: pili, capsule (slime layer), lipid A endotoxin, pyocyanin, exotoxin A, **exoenzymes S and T, elastases, alkaline protease, phospholipase C,** rhamnolipid, **antimicrobial resistance** Diseases: **nosocomial** pathogen; **pneumonia**, **UTI**, medical device infection; skin infection (**hot tub folliculitis**, nails); (malignant) **otitis externa**; **corneal** infection Opportunistic pathogen,usually affects people already in hospital or sick Treatment: double coverage (2 agents of diff classes: **beta lactam plus aminoglycoside** or quinolone)

Question 53

Stenotrophomonas maltophila

Answer 53

Non-fermenter **Nosocomial pneumonia, meningitis, sepsis** Opportunistic infections when impaired host defense

Question 54

Burkholderia cepacia

Answer 54

Non-fermenter **Pneumonia** in cystic fibrosis, **sepsis**, **nosocomial** **UTI** Relatively low virulence

Question 55

Burkholderia pseudomallei

Answer 55

Causes **melioidosis**, skin infection w/adenitis, necrotizing pneumonia w/cavitation Endemic to **Southeast Asia**

Question 56

Acinetobacter

Answer 56

A. baumannii, A. lwoffii, A. haemolytics May be a colonizer **Nosocomial** **pneumonia, sepsis, UTI, wound infection** Antimicrobial resistance

Question 57

Moraxella catharralis

Answer 57

**Bronchopneumonia** in elderly, sinusitis, **otitis media** in kids Produce beta-lactamases

Question 58

Bacteroides fragilis

Answer 58

Gram - rod, aerobic **No activity of LPS!**

Question 59

Anaerobic infection

Answer 59

Usually part of **mixed** **infection** with other gram - or gram + Necrotizing infections, **abscesses** (lung, intra-abdominal, soft tissue, gynecologic)

Question 60

Anaerobic and mixed infection: necrotizing pneumonia, lung abscess,empyema

Answer 60

Rare, but commonly someone aspirating oral secretion Prevotella, porphyromonas, fusobacterium, anaerobic gram + (peptostreptococcus) **Foul smelling breath**, cavitation

Question 61

Anaerobic and mixed infection: brain abscess

Answer 61

**Odontogenic** source, chronic **sinusitis**, **otitis media** Prevotella, porphyromonas, fusobacterium, peptostreptococcus Presents with fever, headache, altered mental status

Question 62

Anaerobic and mixed infection: intra-abdominal infection

Answer 62

Comes from **gut**: perforation of bowel due to trauma, ischemia, diverticulitis, pancreatitis --\> spill intestinal contents into peritoneum **B. fragilis**, B. thetaiotaomicron **Abscess** formation

Question 63

Anaerobic and mixed infection: gynecologic infection

Answer 63

Pelvic inflammatory disease (chlamydia, gonorrhea), tubo-ovarian abscess, salpingitis, endometritis

Question 64

Anaerobic and mixed infection: skin and soft tissue infection

Answer 64

Human bite wound, diabetic foot infection (devitalized tissue due to arterial insufficiency with superimposed infection (wet gangrene)

Question 65

How do you treat anaerobic infection?

Answer 65

**Surgical** **treatment** is critical: must debride and remove necrotic tissue, drain abscesses (poor penetration of antibiotics) **Broad therapy**

Question 66

HACEK organisms

Answer 66

Slow-growing gram - rods Mostly odontogenic source Cause endocarditis, brain abscesses Treat with **ceftriaxone** **Haemophilus aphrophilus** **Actinobacillus actinomycetemcomitans** **Cardiobacterium hominis** **Eikenella corrodens** **Kingella kingae**

Question 67

Pasteurella multocida

Answer 67

Animal borne (get from **cat/dog bites**) Often requires **debridement** or drainage Treat with **amoxicillin/clavulanate (enteral)** or **ampicillin/sulbactam (parenteral)**

Question 68

Bartonella

Answer 68

Slow-growing aerobic gram - Get from **animals**, particularly **insects** B. bacilliformis, B. quintana, **B. henselae**

Question 69

Bartonella bacilliformis

Answer 69

Oroya fever Chronic skin manifestations (verruga) **Sandfly vector**

Question 70

Bartonella quintana

Answer 70

**Trench fever (**common in WWI) Headache, fever for 5 days, weakness, bone pain Person to person spread via **body louse**

Question 71

Bartonella henselae

Answer 71

**Cat-scratch disease** Bacillary angiomatosis in AIDS patients Peliosis hepatis

Question 72

Vibrio vulnificus

Answer 72

**Salt-water** bacteria (surfers!) Skin infection with **bullae**, necrosis; sepsis

Question 73

Vibrio parahaemolyticus

Answer 73

Salt water bacteria (get from **oysters**) Get this in **Japan** Diarrhea, can cause fever

Question 74

Aeromonas

Answer 74

**Water** organism Associated with **wound** **infection** and **enteritis**

Question 75

Plesiomonas shigelloides

Answer 75

**Water** organism Not associated with wound infections Polar flagella

Question 76

Legionellaceae

Answer 76

Gram - rod, slender In water (lakes, streams, **air conditioning**, **respiratory** **devices**) **Intracellular** pathogen **L. pneumophila**, L. micdadei Pathogenesis: binds complement but then prevents fusion with phagolysosome and kills by releasing proteolytic enzymes, phosphatase, lipase, nuclease Diseases: **Legionnaires' Disease**, **Pontiac Fever**

Question 77

Coxiella burnetii

Answer 77

Gram - coccobacillus Intracellular pathogen Associated with farm animals (cows, sheep) Disease: **Q fever** (mild **atypical pneumonia** that can lead to **hepatitis**, **chronic endocarditis**)

Question 78

Typical vs. atypical pneumonia

Answer 78

**Typical**: focal lobar infiltrate (Strep pneumonia, H. influenzae, M. catarrhalis, Strep pyogenes) **Atypical**: patchy infiltrates looks more like viral pneumonia (**legionella**, **chlamydia**, **mycoplasma**)

Question 79

Reasons to use genome sequencing of bacteria

Answer 79

1) Determine the **origin** of bacteria causing an outbreak 2) Determine what **virulence** **factors** bacteria may be using

Question 80

Why wouldn't you want to use an antibiotic that damages DNA (fluoroquinolones) to kill bacteria?

Answer 80

If the bacteria contains a **phage**, it can sense host becoming **damaged** and will make more phage (so more toxin if is phage-encoded) and **escape** the cell

Question 81

Human gut microbes associated with obesity

Answer 81

More **firmicutes** in **obese (fatty)** people and **bacteroidetes** in **skinny** people

Question 82

What is the significance of germ free mice having no gut flora?

Answer 82

**Germ free mice** (no bacteria in gut) **do not get as obese** when over-fed --\> gut microbes modulate energy production and storage