Bacteria Cont, Cell-Wall Antimicrobials (Week 3) Flashcards
Streptococcus pneumoniae
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
What allows us to defend against encapsulated bacteria?
ANTIBODIES!
Complement cannot opsonize/phagocytize/membrane attack complex encapsulated bacteria
Pneumococcal pneumonia
From Streptococcus pneumoniae
Purulent exudate-filled alveoli –> bronchopneumonia, lobar pneumonia, cough
Immunity by antibodies because it is encapsulated (infection or vaccine)
Neisseria meningitidis
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
Drug classes that inhibit cell wall synthesis
Beta-lactam antibiotics: penicillins, cephalosporins; contain 4-membered beta-lactam ring structure
Vancomycin
Bacitracin
Bactericidal; only work on actively proliferating microorganisms
Beta lactam antibiotics
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
Penicillins
Interfere with one of final steps in bacterial cell wall synthesis and cause cell lysis
Can cause hypersensitivity
Transpeptidase
Bacterial enzyme that cross-links peptidoglycan matrix to form cell wall
Located in cytoplasmic membrane
AKA penicillin binding proteins (PBPs)
Bordetella pertussis
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
Clinical features of pertussis (whooping cough)
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
In vaccinated populations, where is the reservoir of B. pertussis?
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
Toxins secreted by B pertussis
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)
Haemophilus influenzae
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
Which pathogens have conjugate vaccines?
Streptococcus pneumoniae
Neiserria meningitis
H. influenza
Note: all encapsulated (duh)
Trimethoprim sulfonamide (TMP/SMX)
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
Important properties of sulfonamides
Highly protein bound
Undergo hepatic metabolism
Metabolite excreted by urine (may form crystals or stones in urinary tract)
Many possible toxicities (SJS)
Drug interaction of sulfonamide and phenytoin
Sulfonamide produces phenytoin toxicity (too much phenytoin) because sulfa binds albumin and displaces phenytoin from albumin
How do bacteria become resistant to sulfonamides?
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
Trimethoprim
Toxicities: nausea and vomiting, hematopoetic problems, interferes with Na/K exchange in kidney (hyperkalemia)
Combination sulfa drugs
Pyrimethamine-sulfadoxine (Fansidar) used to treat malaria
Pyrimethamine-sulfadiazine used to treat toxoplasmosis
Note: sulfa drugs almost never prescribed alone
Use of sulfonamides for other things
Use 1% silver sulfadiazine cream for prophylaxis against infection
Use sodium sulfacetamide drops for conjunctivitis
Where do beta-lactams act?
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
Three groups of cell wall synthesis inhibitors
Beta-lactams
Glycopetides
Inhibitor of peptidoglycan precursor transport (Bacitracin, only used topically)
Resistance to beta-lactams and our response
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 :(
Beta-lactamase inhibitors
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
Beta-lactam toxicity
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)
Vibrio cholerae
Curved gram - rod (comma)
Single polar flagellum for motility
Secretory diarrhea (“rice water diarrhea”)
Transmission is fecal-oral
Cholera toxin is phage-encoded
Campylobacter jejuni
Curved, spiral, gram - rods
Reservoir in wild and domesticated animals
Transmission: contaminated food, water, milk
Common cause of diarrhea
Helicobacter pylori
Most common cause of gastritis and gastric ulcers after NSAIDs
Associated with cancer (gastric adenocarcinoma and gastric (MALT) lymphoma)
Motile
Urease +
Cholera toxin
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
Is cholera caused only by cholera toxin?
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!
Which cephalosporins can cause you to bleed more (increase PT time) and how?
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
What two types of antibiotics can be used synergistically to treat enterococcal infections?
Beta-lactams and aminoglycosides (gentamycin)
(Because beta-lactams might not be fully bactericidal alone)
Salmonella
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
Carrier state of salmonella
Some people infected with salmonella become chronic carriers and have S typhi in their gallbladders
“Typhoid Mary” contaminated food to everyone she cooked for
Shigella
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)
Shiga toxin
Cleaves 28S rRNA, inhibits protein synthesis
Causes cell destruction (usually in GI tract/intestinal epithelial cells) to cause bloody diarrhea
Listeria monocytogenes
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!
Enterobacteriaceae
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
Escherichia coli
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
Different types of E. coli infections
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
Enterotoxigenic E. coli (ETEC)
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)
Enteropathogenic E. coli (EPEC)
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
Enteroinvasive E. coli (EIEC)
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
Enterohemorrhagic E. coli (EHEC)
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
Enteroaggregative E. coli (EAEC)
Chronic watery diarrhea (infants in developing countries; AIDS pts)
Bundle-forming fimbriae AAF-I and -II, no cytotoxin
Not as common
Shiga toxin
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
Klebsiella
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)
Proteus mirabilis
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?
Nosocomial gram negative rods
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))
Pseudomonas aeuginosa
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)
Stenotrophomonas maltophila
Non-fermenter
Nosocomial pneumonia, meningitis, sepsis
Opportunistic infections when impaired host defense
Burkholderia cepacia
Non-fermenter
Pneumonia in cystic fibrosis, sepsis, nosocomial UTI
Relatively low virulence
Burkholderia pseudomallei
Causes melioidosis, skin infection w/adenitis, necrotizing pneumonia w/cavitation
Endemic to Southeast Asia
Acinetobacter
A. baumannii, A. lwoffii, A. haemolytics
May be a colonizer
Nosocomial pneumonia, sepsis, UTI, wound infection
Antimicrobial resistance
Moraxella catharralis
Bronchopneumonia in elderly, sinusitis, otitis media in kids
Produce beta-lactamases
Bacteroides fragilis
Gram - rod, aerobic
No activity of LPS!
Anaerobic infection
Usually part of mixed infection with other gram - or gram +
Necrotizing infections, abscesses (lung, intra-abdominal, soft tissue, gynecologic)
Anaerobic and mixed infection: necrotizing pneumonia, lung abscess,empyema
Rare, but commonly someone aspirating oral secretion
Prevotella, porphyromonas, fusobacterium, anaerobic gram + (peptostreptococcus)
Foul smelling breath, cavitation
Anaerobic and mixed infection: brain abscess
Odontogenic source, chronic sinusitis, otitis media
Prevotella, porphyromonas, fusobacterium, peptostreptococcus
Presents with fever, headache, altered mental status
Anaerobic and mixed infection: intra-abdominal infection
Comes from gut: perforation of bowel due to trauma, ischemia, diverticulitis, pancreatitis –> spill intestinal contents into peritoneum
B. fragilis, B. thetaiotaomicron
Abscess formation
Anaerobic and mixed infection: gynecologic infection
Pelvic inflammatory disease (chlamydia, gonorrhea), tubo-ovarian abscess, salpingitis, endometritis
Anaerobic and mixed infection: skin and soft tissue infection
Human bite wound, diabetic foot infection (devitalized tissue due to arterial insufficiency with superimposed infection (wet gangrene)
How do you treat anaerobic infection?
Surgical treatment is critical: must debride and remove necrotic tissue, drain abscesses (poor penetration of antibiotics)
Broad therapy
HACEK organisms
Slow-growing gram - rods
Mostly odontogenic source
Cause endocarditis, brain abscesses
Treat with ceftriaxone
Haemophilus aphrophilus
Actinobacillus actinomycetemcomitans
Cardiobacterium hominis
Eikenella corrodens
Kingella kingae
Pasteurella multocida
Animal borne (get from cat/dog bites)
Often requires debridement or drainage
Treat with amoxicillin/clavulanate (enteral) or ampicillin/sulbactam (parenteral)
Bartonella
Slow-growing aerobic gram -
Get from animals, particularly insects
B. bacilliformis, B. quintana, B. henselae
Bartonella bacilliformis
Oroya fever
Chronic skin manifestations (verruga)
Sandfly vector
Bartonella quintana
Trench fever (common in WWI)
Headache, fever for 5 days, weakness, bone pain
Person to person spread via body louse
Bartonella henselae
Cat-scratch disease
Bacillary angiomatosis in AIDS patients
Peliosis hepatis
Vibrio vulnificus
Salt-water bacteria (surfers!)
Skin infection with bullae, necrosis; sepsis
Vibrio parahaemolyticus
Salt water bacteria (get from oysters)
Get this in Japan
Diarrhea, can cause fever
Aeromonas
Water organism
Associated with wound infection and enteritis
Plesiomonas shigelloides
Water organism
Not associated with wound infections
Polar flagella
Legionellaceae
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
Coxiella burnetii
Gram - coccobacillus
Intracellular pathogen
Associated with farm animals (cows, sheep)
Disease: Q fever (mild atypical pneumonia that can lead to hepatitis, chronic endocarditis)
Typical vs. atypical pneumonia
Typical: focal lobar infiltrate (Strep pneumonia, H. influenzae, M. catarrhalis, Strep pyogenes)
Atypical: patchy infiltrates looks more like viral pneumonia (legionella, chlamydia, mycoplasma)
Reasons to use genome sequencing of bacteria
1) Determine the origin of bacteria causing an outbreak
2) Determine what virulence factors bacteria may be using
Why wouldn’t you want to use an antibiotic that damages DNA (fluoroquinolones) to kill bacteria?
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
Human gut microbes associated with obesity
More firmicutes in obese (fatty) people and bacteroidetes in skinny people
What is the significance of germ free mice having no gut flora?
Germ free mice (no bacteria in gut) do not get as obese when over-fed –> gut microbes modulate energy production and storage
