Micro midterm Flashcards
Describe how bacteria divide and what features enable them to do so
1) Divide rapidly (exponentially) via transverse fission (splitting apart geometrically)
2A) Actin/tubulin homologues + mitotic apparatus –> chromosome segregation after replication
2B) Cytoskeleton –> to maintain cell shape
Define:
1) Clone
2) Strain
3) Isolate
4) Serotype
1) Clone: population derived from a single cell
2) Strain: clone that is genetically different from other clones of the same species
3) Isolate: clone cultured from a patient with an infection
4) Serotype: clone characterized by specific, important surface structures recognized by the immune system
What is the function and structure of bacterial envelopes
Function: protects bacteria, virulence factor for mammalian cells, target of antibiotics
Structure:
A) Plasma membrane: lipid bilayer eq to mt inner membrane, contains respiratory chain + transport proteins
B) Cell wall: stop water flow into cell –> prevent osmotic lysis; formed by peptidoglycan (inflammatory virulence factor)
C) Structures outside cell wall
1) What is the difference between Gram positive and Gram negative bacteria?
2) How are they ID-ed via Gram stain?
3) What types of bacteria cannot be Gram-stained?
1) Gram positive: peptidoglycan has 20-50 layers
Gram negative: peptidoglycan has 1-3 layers
2) Heat fix bacteria to slide –> stain with Gentian violet dye –> add iodine which complexes/mordants with the dye –> decolorize with alcohol –> counterstain with safranin –> Gram positive is purple; negative is pink
3) Two types of bacteria that cannot be Gram-stained:
A) Acid fast- contain too much lipid for dye to penetrate e.g. Mycobacterium
B) Wall-less- no cell wall e.g. Rickettsia
Compare/contrast the structure of Gram positive vs negative bacterial envelopes
Gram-positive envelopes:
- protein fibrillae/pilli –> anchored to peptidoglycan; for adhesion to cells (virulence factor)
- lipotechoic acids –> sugar polymers linked by phosphates –> structure and stability; bind to TLR to release inflammatory cytokines
- group carbohydrates (only in some)
Gram-negative envelopes:
- outer lipid bilayer membrane external to the cell wall/peptidoglycan; anchored to peptidoglycan via lipoproteins –> highly impermeable, contains endotoxin lipopolysaccharides (LPS) and porin proteins (trimeric barrel to allow passage of solutes)
- periplasm –> space between cell membranes that contains the thin peptidoglycan, carrier proteins, enzymes, etc
What is the structure and function of LPS?
Only on Gram negative bacteria (outer leaflet of outer membrane); LPS = endotoxin
contains 3 parts:
1) O-antigen: long-chain polysaccharide that defends against complement; used to distinguish varieties of bacteria and target for antibiotics
2) Core polysaccharide: units bonded via divalent cations
3) Lipid A: disaccharide + FAs –> toxic when cell lyses open –> LPS binds to TLR –> cytokine storm + hemorrhage + septicemia
Describe bacterial motion and chemotaxis via flagella
Flagella rotate counterclockwise –> drives cell in one direction
Flagella rotate clockwise –> cell tumbles but does not move directionally
Up concentration gradient of attractant –> tumbling suppressed; smooth swimming in one direction
Down concentration gradient of attractant –> tumbling and reorientation promoted
Describe the following bacterial features:
1) S-layer
2) Capsule
3) Spores
1) S-layer: protect layer of protein external to the peptidoglycan
2) Capsule: layer of polysaccharide external to the peptidoglycan –> protects from phagocytosis
Bacteria with capsules are shiny/glistening/smooth; antigenically variable and cannot be visible on Gram stain; K1 capsule disguises E.coli by resembling human cell
3) Spores: made ONLY in Gram positive rods in unfavorable, nutrient-poor conditions; inert (dont grow or divide) and resistant to boiling and disinfecting (have to use autoclave); also do not Gram stain but spore position helps ID bacterial species
Describe two modes of genetic change among bacterial populations
Bacterial populations are clonal, large, and divide rapidly –> mutations have a substantial chance of occurring
1) Spread of favorable mutations via recombination e.g. by using antibiotic
2) Acquisition of genes from unrelated source; mediated by accessory genetic element
Describe accessory genetic elements and highlight which ones are replicons:
1) plasmids
2) viruses (bacteriophage)
3) insertion sequences
4) transposons
5) pathogenicity islands
Replicons: have sites for initiation of DNA synthesis –> chromosomes, plasmids, viruses
1) Plasmids: circular dsDNA, many types and # copies; used to determine if there is common source
2) Viruses: genetic parasite that injects genome into bacteria and uses it to replicate –> lyse cell and release progeny; temperate viruses integrate genome into provirus (latent bc of repressor)
3) Insertion sequence: can move from one location to another between replicons; contain only genes for their transposition (transposase which cleave at inverted repeats)
4) Transposon: contain genes unrelated to transposition e.g. antibiotic resistance genes
5) Pathogenicity islands: large transposons from another species; contains virulence genes (50-100)
* transposition can be either replicative or cut and paste*
Explain how virulence and antibiotic resistance genes are transferred between bacterial cells through:
1) Transformation
2) Conjugation
3) Transduction
Bacterial genome = single circular DNA molecule; DNA transfer is one way, forms merozygote intermediates (complete recipient + donor fragment), and said donor fragment is unstable unless recombined
1) Transformation: donor cell lysed and fragments released, which are taken up by recipient cell; happens naturally in streptococcus, bacillus, neisseria, and haemophilus
2) Conjugation: plasmid DNA copied from F+ and then transferred to F- recipient via conjugation bridge; can also transfer xsomes but much rarer bc it breaks the xsome bridge; R-factor –> F-like plasmid with MDR genes
3) Transduction:
A) Generalized - Virus particle contains bacterial and not viral DNA –> uptake of fragment requires DNA homology
B) Specialized - bacterial gene excised with provirus –> no homology required
Describe antigenic phase variation as a means by which bacteria evade an immune response
Describe three genetic mechanisms responsible for antigenic phase variation:
1) DNA inversion
2) DNA recombination
3) polymerase stuttering
Antigenic phase variation = continual production of new versions of surface antigens –> new forms can escape the immune response and repopulate –> turns off specificity of immune system against it
1) DNA inversion: eg crossover recombination between inverted H repeats for Salmonella flagella –> make either H1 or H2
2) DNA recombination: gene for Neisseria pili has one expressed copy and many silent copies –> recombination between these two homologous types leads to new antigenic versions
3) Polymerase stuttering: Slippage leads to changes in copy number of nucleotide repeat –> IF copy number is not multiple of 3 –> cannot maintain reading frame –> outer membrane Neisseria protein not made –> these cells cannot adhere as well, but cannot be targeted by antibody
Define selective toxicity
Antibiotics target bacterial cells - and not host cells - via unique targets (e.g. cell wall) or preferential target (bacterial ribosome, DHFR–> more selective for prokaryotic vs eukaryotic)
Define:
1) susceptible
2) resistant
3) therapeutic index
4) bacteriostatic
5) bactericidal
1) Susceptible: concentration of drug can be achieved at site of infection that inhibits the organism AND is below toxicity for human cells
2) Resistant: concentration of drug required to inhibit bacterial growth exceeds that which can be achieved safely
3) Therapeutic index: toxic dose / effective dose (better if its larger)
4) Bacteriostatic: inhibits growth but doesn’t kill cells –> can lead to resistance; protein synthesis inhibitors
5) Bactericidal: kills cells and reduces number of bacteria; cell wall active agents
Describe susceptibility testing and what factors influence susceptibility
1A) Dilution test with increasing drug concentration;
MIC = minimal inhibitory concentration
B) Agar test - get aliquots from test tubes and plate to see if there is growth
MBC = minimal bactericidal concentration
If MIC is within therapeutic range of drug, but MBC is not –> bacteriostatic
If MBC is within therapeutic range of drug –> bactericidal
2) Susceptibility influenced by site of infection, local factors (e.g. pH, protein concentration, anaerobic conditions)
Distinguish between therapies:
1) Prophylactic
2) Empiric
3) Definitive
1) Prophylactic: prevent patient from becoming infected e.g. prevent wound infection after surgical procedure
2) Empiric: After symptoms appear but before infecting organism is IDed –> use single broad-spectrum agent to cover all likely pathogens
3) Definitive: After infectious organism defined and susceptibility determined –> Switch to specific, narrow-spectrum agent
Why would drug combination therapy be used? What are the possible effects?
Combination therapy is the exception and not the rule
- Reasons to use:
A) As part of empirical therapy of severe infection when causative organism is unknown e.g. fever of unknown origin
B) treatment of polymicrobial infections
C) Enhance antimicrobial activity for specific infection
D) decrease chance of resistance and reduce toxicity to host - Effects:
A) Synergistic - e.g. bactericidal drugs in combination
B) Additive - e.g. bactericidal drugs in combination
C) Indifferent - using two drugs is the same as using just one
D) Antagonistic - combination less effective than individuals e.g. bacteriostatic + bactericidal drugs
For the following Gram positive cocci bacteria, compare important features (Gram type, colonies, sensitivity, environment):
1) Staphylococci
2) Streptococci
3) Enterococci
1) Staphylococci: Gram positive facultative anaerobes that are arranged in clusters; distinguished from streptococci bc they are catalase positive –> colonies are large, yellow, opaque
Resistant to heat and drying, natural habitat is skin –> nosocomial pathogens (i.e. hospital outbreaks)
2) Streptococci: Gram positive aerotolerant anaerobes that are arranged in long chains; catalase negative –> colonies are small, grey, translucent
Sensitive to heat, drying, cold, starvation; natural habitat is mucous membranes (oral, respiratory, GI, GU)
3) Enterococci: used to be part of Streptococci (part of Group D Streptococci)–> Gram positive aerotolerant arranged in long chains; catalase negative
Hardier than streptococci; natural habitat is mucous membranes (GI)
1) Describe Staph aureus and how it can be IDed
2) Describe S. aureus virulence factors: A. Cell surface B. Cytotoxins (cytolytic exotoxins) C. Invasins (spreading factors) D. Superantigen toxins
1) Staph aureus: type of Staphylococci (Gram positive, catalase positive); most common human pathogen, most often in flora of anterior nares; can ID through golden colonies (with beta hemolysis), ferments mannitol (turns agar yellow), coagulative positive (Activates blood clotting factors)
2) Virulence factors:
A. Cell surface
-Capsule: antiphagocytic microcapsule
-Protein A: on cell wall, anti-opsonic by binding to Fc portions of IgG –> prevents complement activation
-Adhesins: Facilitate attachment to host cells
B. Cytotoxins - target mammalian cell membranes
- Hemolysins (e.g. alpha toxin) –> lyse RBCs
- Leukocidin –> destroys neutrophils
C. Invasins - penetration through extracellular tissue
- Staphylokinase
- Hylarunodiase
- Lipase (e.g. beta toxin) –> damages RBCs
D. Superantigen toxins - nonspecific binding of MHC II and TCRs –> cytokine storm
- TSST (toxic shock syndrome toxin)
- Enterotoxin (food poisoning from food left out too long E.G. mayo)
- Exfoliatin (scalded skin syndrome)
For S. Aureus, describe:
1) Clinical manifestations/diseases caused
2) Treatment
1) Clinical manifestations
A. Skin and soft tissue infections - abscess + pus e.g. furuncles, carbuncles, impetigo, cellulitis
B. Infections: Bone=Osteomyelitis (S. aureus is most common cause); Joint fluid = Septic arthritis; Blood= bacteremia and septicemia
C. Pneumonia following viral infections
D. Acute endocarditis (tricuspid valve) - associated with IV drug use
E. Superantigen toxinoses - TSS (due to TSST), gastroenteritis (due to enterotoxin, acute onset with projectile vomiting), scalded skin syndrome (due to exfoliatin)
2) Treatment
- 2nd generation penicillin (penicillinase-resistant beta lactam antibiotic) used to disrupt cell wall synthesis –> use nafcillin (“Naf for Staph”)
- MRSA acquires resistance to all beta lactam antibiotics by altering penicillin-binding proteins (PBP)–> use vancomycin to treat
Of the coagulase negative Staphylococci (epidermidis and saprophyticus), describe:
1) How they can be IDed
2) Virulence factors
3) Clinical manifestations
4) Treatment
I. S. epidermidis –> part of normal skin flora
1) ID: Clustered Gram positive cocci, catalase positive, coagulase negative
2) Virulence factors: produces polysaccharide cell surface slime and adheres to bioprosthetics, acts as barrier to antibiotics and immune cells
3) Clinical Manifestations: Nosocomial infections e.g. prosthetic joints, catheters, IV lines; endocarditis of artificial heart valves (S. epidermidis is most common cause)
4) Treatment: Vancomycin (resistant to penicillin)
II. S. saprophyticus - part of normal vaginal flora
1) ID: Clustered Gram positive cocci, catalase positive, coagulase negative, Novobiocin antibiotic resistance
2) Virulence factors: extracellular slime, adhere to uroepithelial cells via lipotechoic acid
3) Clinical Manifestations: UTI, cystitis in women
4) Treatment: Penicillin G
How are streptococci classified via hemolysis and Lancefield Groups?
1) Hemolysis: strep causes destruction of RBCs
- Beta hemolytic: produce proteins that cause complete RBC destruction –> see ring
- Alpha hemolytic: produce H202 to damage cell membrane –> greenish/brown discoloration of heme
- gamma hemolytic: no hemolysis
2) Lancefield: classified based on C substance (antigenic cell wall polysaccharide)
- A e.g. S. pyogenes (beta hemolytic) –> bacitracin sensitive
- B e.g. S. agalactiae (beta) –> bacitracin resistant
- D e.g. Enterococcus faecalise, S. bovis (alpha or gamma)
- None e.g. Viridans (on oral flora; alpha), S. pneumoniae (i.e. pneumococcus; alpha)
Group A Streptococci (GAS) - S. pyogenes:
1) How they can be IDed
2) Virulence factors
3) Clinical manifestations
4) Treatment
GAS e.g. S. pyogenes –> in throat, nasopharynx
1) ID: Gram positive streptococci + catalase negative; beta hemolytic, bacitracin sensitive; capsule of hyaluronic acid but its not immunogenic (since we have HA in our collagen)
2) Virulence:
A. M protein - antiphagocytic (prevents opsonization), inhibits complement
B. Streptolysin O (SLO) - lyse RBCs; retrospective diagnosis by detecting antibodies to SLO (i.e. ASO)
C. Streptokinase - activates plasmin to dissolve clots
D. SPExotoxins - superantigen toxins (SPEs A and C) cause scarlet fever, TSS; SPE B causes necrotizing fasciitis
3) Clinical manifestations:
A. Pyogenic infection (caused by bacteria)
-pharyngitis (strep throat)
-SSTI - impetigo (honey-crusted skin infection)
-Erysipelas - demarcated, superficial cellulitis –> skin infection with raised red patches and rash (S. pyogenes is most common cause) + cellulitis
B. Exotoxin (SPE) infections
-Scarlet fever - strawberry tongue, pharyngitis, skin rash everywhere except the phase
-Toxic shock-like syndrome
-necrotizing fasciitis
4) Treatment:
- Penicillin G for strep throat
- Penicillinase-resistant penicillin (e.g. oxacillin) for skin infections
Describe the clinical sequelae of untreated infections for Group A Streptococci i.e. S. pyogenes:
1) Acute rheumatic fever
2) Glomerulonephritis
1) Acute rheumatic fever: 2-3 weeks post pharyngitis only
- Type II Hypersensitivity: molecular mimicry Ab-mediated humoral response against myosin, which resembles M protein –> mitral damage, myocarditis
- Other clinical manifestations: JONES criteria–> J=joint arthritis, O=cardiac problems, N = subcutaneous nodules, E =erythematous rash (erythema marginatum), S = Sydenham’s chorea
- CAN be prevented by early treatment of strep throat with penicillin
2) Glomerulonephritis: 1-2 weeks post pharyngitis OR skin infection e.g. impetigo
- Type III Hypersensitivity: Ab-Ag complexes
- Clinical: fluid retention/hypervolemia –> facial puffiness, hematuria (Cola-colored urine)
- CANNOT be prevented by early treatment of strep throat with penicillin
Group B Streptococci (GBS) - S. agalactiae:
1) How they can be IDed
2) Virulence factors
3) Clinical manifestations
4) Treatment
GBS - S. agalactiae –> normal flora of female reproductive tract
1) ID: Gram positive streptococci + catalase negative; beta hemolytic, bacitracin resistant; positive hippurate and CAMP tests (increasing zone of hemolysis when plated with Staph aureus, distinguishes S. agalactiae among all other streps)
2) Virulence: antiphagocytic capsule
3) Clinical: #1 cause of neonatal meningitis, sepsis; also causes pneumonia
4) Treatment: Women screened for GBS colonization at 35 weeks; mom treated prophylactically with intrapartum Penicillin G
Enterococci (E. faecalis/faecium) + Group D Streptococci (S. bovis)
1) How they can be IDed
2) Virulence factors
3) Clinical manifestations
4) Treatment
E. faecalis + E. faecium (Enterococci) and S. bovis (GDS non-enterococci) –> part of normal GI flora
1) ID: Gram positive streptococci + catalase negative; alpha or gamma hemolytic
- Enterococci –> grow in both 40% bile salt (bile resistant) or 6.5% NaCl
- Non-enterococci (S. bovis)–> grow in 40% bile but NOT in 6.5% NaCl
2) Virulence: None to remember
3) Clinical: E. faecalis is more common, E. faecium more dangerous
- E. faecalis and E. faecium–> UTI
- S. bovis –> endocarditis, biliary tract infection, bacteremia (Associated with colon cancer!)
4) Treatment: first-line is ampicillin + gentamycin (resistant to penicillin), second-line is vancomycin; enterococci in particular are MDR incl. vancomycin resistant (VRE)–> linezolid, pristinamycin, or tigecycline
“Non-Lancefield” Group Streptococci - Viridans e.g. S. mitis
1) How they can be IDed
2) Virulence factors
3) Clinical manifestations
4) Treatment
Viridans group - normal flora in upper respiratory tract, oral cavity e.g. S. mitis: in oral cavity
1) ID: Gram positive streptococci + catalase negative; alpha hemolytic; resistant to bile salt + optochin, 6.5% NaCl
2) Virulence: Unencapsulated; adheres to platelets by creating dextrans from glucose
3) Clinical:
- Dental caries
- Subacute endocarditis - form vegetations on artificial or damaged mitral valves; common in IV drug users who lick the syringe (Ew)
4) Treatment: Penicillin G, synergistic with aminoglycosides
“Non-Lancefield” Group Streptococci - S. pneumoniae
1) How they can be IDed
2) Virulence factors
3) Clinical manifestations
4) Treatment
S. pneumoniae i.e. pneumococci –> in oropharynx
1) ID: Gram positive streptococci + catalase negative; lancet cells grouped in pairs; alpha hemolytic; bile soluble and sensitive to optochin (cannot grow in presence of either bile or optochin)
2) Virulence: antiphagocytic polysaccharide capsule (85+ serotypes) –> increased risk in asplenics; also has IgA protease
3) Clinical: Most common bacterial cause of MOPS (meningitis, otitis media esp in kids, pneumonia, and sinusitis)
- Pneumonia - lower lobes, rust-colored sputum
- Otitis media - noncapsulated, less virulent bacteria
- Meningitis -
- Sinusitis or septicemia - bacteria in the bloodstream
4) Treatment:
- Penicillin G (non-CNS)
- Cefotaxamine, Ceftriaxone (CNS antibiotic)
- PPV vaccine - antibodies against capsule for at-risk (sickle-cell or other asplenics, children, alcoholics, elderly); adult version is IgM and childrens is IgG bc conjugated to protein
Describe the overall identifying features of Gram negative cocci - Neisseria:
1) Structural features
2) Environment
3) Virulence factors
4) Pathogenesis
Neisseria
1) Structural: Gram negative diplococci; often seen with neutrophils upon Gram stain; culture on Thayer-Martin chocolate agar with antibiotics
2) Environment:
- oxidase positive –> aerobic
- sensitive to heat, drying
- only grow on chocolate agar or VPN agar (NOT blood agar)
3) Virulence factors:
- pili/fimbriae with many antigenic variants –> evading immune system
- IgA protease –> survival along mucosal surfaces
- iron-binding proteins (lactoferrin and transferrin)
- Opa proteins on outer membrane –> for adhesion
- LOS endotoxin (not LPS, since carb chains are shorter than in other Gram negative species)
4) Pathogenesis:
- complement deficiencies (C5-C9) –> cannot make MAC –> Neisseria
- pyogenic cocci –> infection has pus
- mechanism: adhesion via pili and Opa proteins –> bacteria internalized –> transocytosis (enter submucosal space via epithelial cell) –> hypovolemia
N. gonorrhoeae (gonococci):
1) How they can be IDed
2) Virulence factors
3) Clinical manifestations
4) Epidemiology
5) Treatment/Prevention
N. gonorrhoeae - 1 strain; in mucous membranes (GU, eye, rectum, throat)
1) ID: Gram negative diplococci, oxidase positive, sensitive to normal human serum –> cannot multiple; ferments only glucose (N. meningitidis also ferments maltose)
2) Virulence factors:
- unencapsulated (N. meningitidis has capsule)
- Same features as N. meningitidis–> LOS endotoxin, pili, Opa, iron binding proteins, IgA protease
3) Clinical manifestations:
- GU tract infections - Gonorrhea: (men) urethritis, (women) cervicitis –> pelvic inflammatory disease –> infertility
- thick white pus discharge, rectal infections, polyarthritis of one knee
- ophthalmia neonatorum - pinkeye in babies within 5 days of birth; give silver nitrate
- bacteremia is rare bc cannot grow in bloodstream
4) Epidemiology: STD, many times asymptomatic but still infectious; infection increases risk of HIV
5) Treatment: gonococci penicillin resistant –> 3rd gen cephalosporin antibiotic (ceftriaxone) + macrolide (azithromycin/doxycycline) for concomitant Chlamydia; IV ceftriaxone for opthalmia neonatorum
N. meningitidis (meningococci):
1) How they can be IDed
2) Virulence factors
3) Clinical manifestations
4) Epidemiology
5) Treatment/Prevention
N. meningitidis - 3 strains; in nasopharynx, transmitted via respiratory secretions
1) ID: Gram negative, oxidase positive, can grow well in bloodstream; can ferment glucose AND maltose (N. gonorrhea only ferments glucose)
2) Virulence factors:
- antiphagocytic capsule - can switch expression of serogroups via transformation
- others are same as in N. gonorrhoeae (endotoxin via LOS, IgA protease, pili, Opa, iron binding proteins)
3) Clinical:
-LOS endotoxin (envelope proteins) –> inflammatory response –> leakage of fluid from capillaries –> hypovolemia and shock
-Meningococcemia - bacteria in bloodstream –> characteristic petechial rash, fever, chill, joint pain –>
A. FMS/Waterhouse-Friderichsen Syndrome- adrenal hemorrhage –> worsens LOS-mediated septic shock + DIC (disseminated intravascular coagulation) –> death before meningitis can develop
or B. Meningitis - pus in CSF, stiff neck, vomiting, headache
4) Epidemiology: 5-10% are carriers; most commonly affected is longer lasting immunity
5) Treatment: 3rd gen cephalosporin (ceftriaxone); rifampin prophylaxis for close contacts
Describe the four mechanisms that form the genetic basis of resistance:
- Transformation
- Transduction
- Conjugation
- Transposition
- Transformation: small pieces of DNA that encode for resistance taken up and incorporated into genome
- Transduction: resistance genes transferred from one bacterium to another via bacteriophage virus
- Conjugation: resistance genes transferred directly from one bacterium to another via pilus
- Transposition: resistance genes move between plasmid and chromosome via enzymes
Describe the biochemical mechanisms of drug resistance (mostly applicable to Gram negative):
- Decreased intracellular drug level
- Increased inactivation of drug
- Decreased conversion of drug to active compound
- Increased concentration of antagonistic metabolite
- Altered amount of target enzyme/receptor
- Decreased affinity of receptor for drug
- Decreased activity of required enzyme for drug effect
- Decreased intracellular drug level
- altered porins –> Decreased drug entry
- Gram negative pumps –> increased drug efflux - Increased inactivation of drug
- bacteria can produce enzymes to inactivate drugs e.g. Beta lactamase –> hydrolyzes beta lactam ring of penicillins and cephalosporins
- enzymatic modification of aminoglycosides - Decreased conversion of drug to active compound
- seen in antimetabolite drugs which have to be activated
- arises via mutation and selection - Increased concentration of antagonistic metabolite
- increased production of endogenous metabolite competes with drug for binding –> leads to resistance - Altered amount of target enzyme/receptor
-mutation in repressor of target
resistance plasmids contain multiple copies of target gene - Decreased affinity of receptor for drug
- mutation in target receptor that changes conformation of drug binding site –> reduces affinity e.g. trimethoprim resistance - Decreased activity of required enzyme for drug effect
- deficiency in autolytic enzymes –> turns cell wall inhibitors from bacteriocidal into bacteriostatic
What are factors that contribute to drug resistance?
- genetic change via mutation or gene transfer
- drugs provide selective pressure for resistant strains to grow –> only 10% of initial population needs to be resistant to spread
- bacteriostatic drugs increase probability of mutations bc they dont kill the bacteria –> much shorter shelf-life than bacteriocidal drugs
- antimicrobial resistance more common in strains that case nosocomial infections e.g. Staph
- areas in hospitals with highest antibiotic use e.g. ICU, ER have highest incidence of drug-resistant bacteria
- patients with resistant strains more likely to have received prior antimicrobial therapy
List overal mechanism of action of each class of antibiotics and specific drugs in each:
1) Protein synthesis inhibitors
A. 30S rb subunit inhibitors
B. 50S rb subunit inhibitors
2) DNA synthesis inhibitors
A. Antifolate drugs
B. DNA gyrase/Topo IV inhibitors
1) Protein synthesis inhibitors - inhibit 70S bacterial ribosomes
A. 30S rb subunit inhibitors
-aminoglycosides e.g. streptomycin, gentamicin, neomycin
-tetracyclines e.g. tetracycline, doxycycline, tigecycline
B. 50S rb subunit inhibitors
- macrolides –> most common e.g. erythromycin, azithromycin, calrithromycin
- Other, less commonly used: lincosamide (e.g. clindamycin), streptogramin (e.g. dalfopristin), oxazolidinone (e.g. linezolid)
2) DNA synthesis inhibitors
A. Antifolate drugs - inhibit biosynthesis of purine bases and thus DNA
-sulfonamides e.g. sulfamethoxazole
-trimethoprim, usually via TMP-SMX combo e.g. Bactrim, Septra
B. DNA gyrase/Topo IV inhibitors - block DNA replication by inhibiting bacterial topoisomerase II (DNA gyrase) and topoisomerase IV
-fluoroquinolones e.g. ciprofloxacin
Protein synthesis inhibitors –> 30S inhibitors –> Aminoglycosides:
1) Spectra of antibiotic activity (bactericidal vs bacteriostatic)
2) MOA
3) Clinical uses
4) Most common adverse reactions
Aminoglycosides
1) Bactericidal against aerobic Gram negative bacteria (unique among proteins synthesis inhibitors, which are mostly bacteriostatic); have post-antibiotic effect (can kill bacteria after drug has been eliminated)
2) MOA: Binds to 30S subunit of bacterial ribosome and:
A. blocks initiation of protein synthesis
B. elicits premature termination of translation
C. incorporates incorrect AA –> kills bacteria
3) Clinical uses:
A. Streptomycin - 2nd line agent for TB in combination with INH or rifampin
B. Gentamicin (less $$) and tobramycin - severe infection by resistant Gram negative bacteria, in combo with B-lactam drug for synergy/preventing resistance
C. Amikacin - for bacteria resistant to gentamicin and tobramycin
D. Neomycin and kanamycin - topical use e.g. skin (Neosporin), eye drops (Neocin) bc toxic
4) Adverse rxns:
A. Nephrotoxicity - more likely >5 days treatment, reversible when treatment finished
B. Ototoxicity - auditory (tinnitus), vestibular (vertigo/ataxia); irreversible
Protein synthesis inhibitors –> 30S inhibitors –> Tetracyclines:
1) Spectra of antibiotic activity (bactericidal vs bacteriostatic)
2) MOA
3) Clinical uses
4) Most common adverse reactions
Tetracyclines
1) Bacteriostatic for aerobic and anaerobic Gram positive and negative bacteria, also protozoa
2) MOA: binds to 30S ribosomal subunit and prevents peptide elongation at the A site; tetracycline properties similar except for pharmacokinetics
3) Clinical uses:
A. Doxycycline - longer half-life (1x day); anthrax, malaria, early stage lyme disease
B. Tigecycline - longest half-life, IV administration; severe MDR cases, community-acquired pneumonia
C. All tetracyclines - rickettial infections (e.g. typhus, Rocky Mountain), STIs (e.g. chlamydia, cervicitis), skin and soft tissue infections (e.g. community-acquired Staph, severe acne), respiratory tract infections
4) Adverse rxns:
A. GI upset - nausea, vomiting, diiarrhea
B. Bind calcium esp in kids - grey teeth, brittle bone
C. Photosensitivity
D. Liver disturbance –> contraindicated in pregnancy
Protein synthesis inhibitors –> 50S inhibitors –> Macrolides:
1) Spectra of antibiotic activity (bactericidal vs bacteriostatic)
2) MOA
3) Clinical uses
4) Most common adverse reactions
Macrolides
1) Bacteriostatic for aerobic Gram positive bacteria (some negative)
2) MOA: Bind to 50S ribosomal subunit and inhibit translocation step of protein synthesis; properties similar except for pharmacokinetics (azithromycin has longest half life)
3) Clinical uses:
A. Respiratory tract infections - pneumonia (S. pneumoniae, M. pneumoniae, L. pneumophila)
B. Skin and soft tissue infections - substitute for penicillin in allergic individuals with Staph infections
C. Acute otitis media
D. Streptococcal pharyngitis (Strep throat)
E. Chlamydia
F. Diptheria and pertussis (whooping cough)
4) Adverse rxns:
A. GI upset - anorexia, nausea, vomiting, diarrhea
B. Hepatotoxicity - acute cholestatic hepatitis
Protein synthesis inhibitors –> 50S inhibitors –> Others
(lincosamide, streptogramin, oxazolidinone):
1) Spectra of antibiotic activity (bactericidal vs bacteriostatic)
2) MOA
3) Clinical uses
4) Most common adverse reactions
Lincosamide e.g. clindamycin
1) Bacteriostatic for aerobic and anaerobic Gram positive bacteria
2) MOA: Binds 50S and inhibits translocation
3) Uses: Skin and soft tissue infections
4) Adverse rxns: pseudomembranous colitis caused by C. difficile, skin rashes, diarrhea
Streptogramin e.g. quinupristin/dalfopristin (IV combo)
1) Bactericidal for strep and staph, but bacteriostatic for enterococci
2) MOA: Binds 50S and inhibits translocation
3) Uses: skin infections caused by MSSA, infections caused by vancomycin-resistant E. faecium
Oxazolidinone e.g. linezolid
1) Bactericidal for strep, but bacteriostatic for staph and enterococci
2) MOA: Binds 50S and blocks initiation of translation
3) Uses: Infections caused by MDR Gram positive bacteria e.g. MRSA, VRE
DNA synthesis inhibitors –> Antifolates –> Sulfonamides (SMX):
1) Spectra of antibiotic activity (bactericidal vs bacteriostatic)
2) MOA
3) Clinical uses
4) Most common adverse reactions
Sulfonamides
1) Bacteriostatic vs Gram negative (Some positive); bactericidal in combo with DHFR inhibitor (trimethoprim)
2) MOA: PABA analog that competitively inhibits enzyme that converts PABA to dihydrofolic acid
3) Uses (usually used in combo):
A. Sulisoxazole and sulfamethoxazole - UTI
B. Sulfasalazine - IBD e.g. ulcerative colitis
4) Adverse rxns:
A. Allergic rxns e.g. fever, rashes, urticaria, photosensitivity
B. Precipitate in urine –> crystalluria, hematuria
DNA synthesis inhibitors –> Antifolates –> Trimethoprim (TMP):
1) Spectra of antibiotic activity (bactericidal vs bacteriostatic)
2) MOA
3) Clinical uses
4) Most common adverse reactions
Trimethoprim, via TMP-SMX (sulfonamide) combo
1) TMP is bacteriostatic; TMP-SMX combo is bactericidal
2) MOA: Competitive inhibitor of bacterial dihydrofolate reductase enzyme (less effective at inhibiting mammalian DHFR)
3) Uses: UTI, salmonella, shigellosis, prostatitis, pneumocystis jiroveci pneumonia, acute exacerbation of chronic bronchitis
4) Adverse rxns:
A. less than 5 days - allergic rxns w/ rash, fever, GI upset
B. more than 5 days - hematologic e.g. megaloblastic anemia, leukopenia
DNA synthesis inhibitors –> Topo inhibitor –> Fluoroquinolones (FQs):
1) Spectra of antibiotic activity (bactericidal vs bacteriostatic)
2) MOA
3) Clinical uses
4) Most common adverse reactions
Fluorquinolones
1) Bactericidal vs Gram positive (DNA gyrase) and negative (topo IV) bacteria
2) MOA:
A. Inhibits bacterial topo II (DNA gyrase) –> inhibits relaxation of positive supercoiled DNA during replication
B. Inhibits bacterial topo IV –> inhibits separation of chromosomal DNA into daughter cells during cell division
3) Uses:
A. UTI - even when caused by MDR bacteria
B. Diarrhea caused by shigella, salmonella, e. coli
C. soft tissue, bone, joint infections
D. Cipro - prophylaxis/treatment of anthrax
E. Respiratory FQs (levofloxacin, gemifloxacin, moxifloxacin) - upper and lower respiratory tract infections
4) Adverse rxns: generally well tolerated
A. GI upset - nausea, vomiting, diarrhea
Compare the structures and members of the Gram negative bacilli enteropathogen groups:
1) Enterobacteriaceae
2) Vibrionacae
3) Campylobacter and Helicobacter
1) Enterobacteriaceae: short, thick rods; petrichous (uniformly distributed flagella); oxidase negative
- Salmonella, shigella, yersinia, E. coli, etc.
2) Vibrionacae: curved rods (comma-shaped), polar flagella, oxidase positive
- cholera
3) Campylobacter and Helicobacter: curved rods, not closely related to #1 or 2
* other intestinal pathogens include Clostridium, viruses, and protozoa
