Introduction to Infectious Diseases Part 2 Flashcards

Question

Gram positive and gram negative cell overview

Answer 1

gram positive: thick peptidogylcan wall, semi-permeable membrane, beta-lactamases located in extracellular space gram negative: thin peptidoglycan wall, contain porins to let drugs through, beta-lactamases in periplasmic space, contain lipopolysaccharides (endotoxins)

Answer 2

cytoplasmic membrane, peptidoglycan layer, outer membrane, periplasmic space

Answer 3

acts as selective barrier certain drugs must pass through to reach target site

Answer 4

GP: thick, GN: thin permeability barrier for large molecules PBPs: proteins essential for cell-wall synthesis

Answer 5

lipopolysaccharides: mediator of immune response and sepsis porins: hydrophilic chanels the permit diffusion of essential nutrients and small hydrophilic molecules

Answer 6

compartment between cell membrane and cell wall (GP) or between cell membrane and outer membrane (GN) vital for bacterial protein secretion, folding, quality control; acts as reservoir for virulence factors

Answer 7

these are enzymes vital for cell wall synthesis, cell shape, and structural integrity - transpeptidases, carboxypeptidases, endopeptidases differ from one bacterial species to another binding to PBPs 1A, 1B, 2, and 3 result in bactericidal effect transpeptidase most important PBP - catalyzes the final cross linking in the peptidoglycan structure

Answer 8

always resistant to given antibiotic (naturally resistant) MOA: absence of target site, bacterial cell impermeability ex. cephalosporins vs enterococci; beta-lactams vs mycoplasma

Answer 9

initially susceptible but develop resistance due to some mechanism MOA: mutation in bacterial DNA (spontaneously vs selective pressure); asquisition of new DNA (chromosomal or extrachromosomal plasmid) ex. stable depression of AmpC; acquisition of KPC gene in GNRs

Answer 10

self-replicating, extrachromosomal DNA; transferable between organisms

Answer 11

genetic elements capable of translocating from one location to another; move from plasmid to chromosome or vice versa

Answer 12

viruses that can transfer DNA from organism to organism

Answer 13

direct contact or mating via sex pili most common

Answer 14

transfer of genes between bacteria by bacteriophage

Answer 15

transfer or uptake of "free floating" DNA from the environment

Answer 16

4 different mechanisms: 1. altered cell wall protein/decreased porin production 2. efflux pump (pump it out) 3. drug-inactivating enzyme 4. modified drug target don't let it in, pump it out, chew it up, change it up

Answer 17

enzymes that hydrolyze beta-lactam ring by splitting amide bond: inactivates drugs two classification systems: ambler class, bush-jacoby medeiros

Answer 18

serine beta-lactamase: serine residue at active site metallo-beta lactamases: zinc residue at active site

Answer 19

serine active site creates acyl-enzyme complex through acylation --> through de-acylation, we open up the beta-lactam ring --> opening it up inactivates the beta-lactam antibiotic restores beta-lactamase

Answer 20

open up the ring and inactivate the beta-lactam antibiotic

Answer 21

extended spectrum beta lactamases (ESBL) serine carbapenemases metallo-beta-lactamases cephalosporinases OXA-type

Answer 22

CTX-M-15 hyrdolyze narrow and extended spectrum beta-lactam antibiotics (bacteria that carry these enzymes are resistant to these antibiotics)

Answer 23

KPC-1, KPC-2, KPC-3 hydrolyze carbapenems, cephalosporins, and penicillins

Answer 24

NDM-1 hydrolyze carbapenems

Answer 25

Amp-C inducible

Answer 26

OXA-48 hydrolyze oxacillin, oxyimino beta-lactams, and carbapenems

Answer 27

Plasmid-mediated enzymes that hydrolyze most penicillins, cephalosporins, and monobactams - Do not inactivate non-beta-lactam agents (eg. ciprofloxacin, doxycycline, gentamicin); Organisms with ESBL genes often harbor additional resistance genes CTX-M enzyme most common: Most prevalent in Escherichia coli, Klebsiella pneumoniae/oxytoca, and Proteus mirabilis; Ceftriaxone non-susceptibility Treatment of choice: Carbapenems (meropenem, imipenem, doripenem, ertapenem) Piperacillin/tazobactam an option for urinary source only

Answer 28

Most frequent cause of Carbapenem-resistant Enterobacterales (CRE) - Resistance to whole beta-lactam class Klebsiella pneumonia carbapenemase (KPC) - Plasmid-mediated enzyme; KPC-2 & KPC-3 most common variants; Found in: K. pneumoniae, K. oxytoca, E.coli, E. cloacae, E. aerogenes, P. mirabilis Treatment options: ◦ β-lactam: ceftazidime/avibactam, meropenem/vaborbactam, imipenem/cilastatin/relebactam ◦ Non β-lactam: Plazomicin, eravacycline, omadacycline

Answer 29

Confer resistance to all β-lactams except monobactams (aztreonam) - Harbor additional antibiotic-resistance genes to other antimicrobial classes Examples: New Delhi MBL (NDM) - Present in P. aeruginosa, Acinetobacter spp, and Enterobacterales Treatment options: Limited!; Not inhibited by any current β-lactamase inhibitors; Cefiderocol; aztreonam + ceftazidime/avibactam

Answer 30

Large heterogenous group often accompanied by other beta-lactamase classes (e.g., co-expression of ESBLs and AmpC) Primarily found in Acinetobacter baumannii (A. baumannii), Pseudomonas aeruginosa and some Enterobacterales, such as Klebsiella pneumonia Treatment options: Extremely limited; Cefiderocol; Sulbactam/durlobactam

Answer 31

Three different mechanisms: ◦ 1) inducible via chromosomally encoded AmpC genes ◦ 2) Non-inducible chromosomal resistance via mutations (rare) ◦ 3) Plasmid-mediated resistance Not inhibited by older β-lactamase inhibitors (clavulanic acid, tazobactam, sulbactam); Inhibited by newer β-lactamase inhibitors: avibactam, vaborbactam, relebactam Found in: Hafnia alvei, Enterobacter cloacae, Citrobacter freundii, Klebsiella aerogenes, Yersinia enterocolitica (HECK-YES); Also in Serratia marcescens, Morganella morganii, Aeromonas hydrophilaà HECK-YES Ma’aM Referred to as AmpC or inducible organisms

Answer 32

Transient elevation in enzyme production in the presence of certain beta-lactam agents Initially, gene for beta-lactamase production is repressed --> inducer --> gene derepressed --> increased beta-lactamase production Remove inducer --> gene repressed --> beta-lactamase production back to low level Genetic mutation --> gene derepressed --> stable derepression --> high level beta-lactamase production continuously Different beta-lactams induce AmpC beta-lactamases to varying degrees

Answer 33

ceftriaxone is a weak inducer, with high susceptibility to ampC hydrolysis cefepime is a weak inducer, with low susceptibility to ampC hydrolysis carbapenems (imipenem, meropenem, ertapenem) are strong inducers, with low susceptibility to ampC hydrolysis cefepime is 1st line --> carbapenems

Answer 34

Treatment: Cefepime(1st-line), Carbapenems, Non-β-lactams (Fluoroquinolones, trimethoprim/sulfamethoxazole, tetracyclines)

Answer 35

Most common method of aminoglycoside resistance 3 mechanisms: Acetylation, Nucleotidylation, Phosphorylation Modify aminoglycoside structure by transferring the indicated chemical group to a specific side chain --> impairs cellular uptake and/or binding to ribosome Nomenclature based on chemical group transferred and site of transfer Bifunctional enzyme --> acetylation and phosphorylation of aminoglycoside Seen in Enterococci --> high level of gentamicin resistance

Answer 36

Mechanism of vancomycin resistance in Enterococci species Vancomycin binds to D-Alanine-D-Alanine terminus of peptidoglycan precursors: Inhibits cell wall synthesis Resistance alters D-Ala-D-Ala to D-Ala-D-Lac or D-Ala-D-Ser: Mediated by VanA or VanB gene --> most common; Produces vancomycin-resistant enterococcus (VRE) Treatment: Daptomycin or linezolid

Answer 37

Alterations in PBPs leads to β-lactam resistance Due to decreased affinity of PBPs for antibiotic or change in amount of PBP produced by bacteria - Addition of β-lactamase inhibitor is ineffective in restoring activity of β-lactam antibiotic Methicillin-resistant Staphylococcus aureus (MRSA): Resistance due to expression of mecA gene (mecA + = PBP2A + = MRSA) ◦ Encodes for PBP2A --> low affinity for beta-lactam antibioticsà resistance to β-lactam class with 2 exceptions (see below) Treatment: Ceftaroline, Ceftobiprole; vancomycin, daptomycin, linezolid Streptococcus pneumoniae: Alteration in PBP confers penicillin and cephalosporin resistance

Answer 38

Responsible for macrolide resistance in S. pneumoniae: ermB gene --> cross resistance with clindamycin Aminoglycoside resistance in Gram negatives Clindamycin resistance

Answer 39

Responsible for Fluoroquinolone (ciprofloxacin, levofloxacin) resistance in Gram-negative and S. pneumoniae

Answer 40

actively transport antibiotics OUT of periplasmic space: overexpression can lead to high-level of resistance; Efflux is important for a range of antibiotic classes Important resistance mechanism for P. aeruginosa against carbapenems & S. pneumoniae against macrolide antibiotics

Answer 41

are hydrophilic diffusion channels Rate of antibiotic diffusion depends on porin & antibiotic physiochemical characteristics - smaller, more hydrophilic antibiotics pass easier than larger, hydrophobic antibiotics Mutations result in loss of specific porins --> leads to antibiotic resistance - Most commonly seen with Enterobacterales and carbapenem-resistant P. aeruginosa

Answer 42

In vitro terms not based on linkage to any predictive ability in vivo Not always a clear distinction: some bactericidal drugs may be static against certain organism and vice versa Bactericidal agents still preferred for certain infections (meningitis, endocarditis) Important to optimize dose based on patient factors, site of infection, and organism

Answer 43

Exert effect when concentrations well above organism’s MIC: ↑Cmax/MIC = greater killing --> correlates with increased AUC Some agents, such as fluoroquinolones and aminoglycosides exhibit PAE: Gram-positive and Gram-negative bacteria Fluoroquinolones (Levofloxacin, Ciprofloxacin): Concentration-dependent bactericidal activity --> fAUC0-24/MIC Aminoglycosides (Gentamicin, Tobramycin, Amikacin): Concentration-dependent bactericidal activity --> Cmax/MIC; Optimal dosing achieved through TDM and use of high dose extended interval

Answer 44

All β-lactam antibiotics (penicillin, cephalosporin, carbapenem, monobactam) Time that free drug concentrations remain above MIC correlates with clinical and microbiological outcomes (fT>MIC) fT>MIC Penicillin: 50% fT>MIC Cephalosporin: 60-70% fT>MIC Carbapenem: 40% Antibacterial properties: Not rapidly bactericidal; Time-dependent bactericidal activity; Little to no PAE

Answer 45

Maximize fT>MIC (as a % of dosing interval): Gram-negatives: Carbapenems: ≥40%; Penicillins: ≥50%; Cephalosporins: ≥ 60%; Gram-positive: ≥40-50% Strategies to maximize fT>MIC: Increase dose, same interval (1g Q8h vs. 2g q8h); Same dose, shorter interval (1g Q12h vs. 1g Q6h); Continuous infusion: Stability issues; need dedicated IV line Prolonged infusions: Infuse dose over 3-4 hours; Provides longer T>MIC than traditional infusions

Answer 46

Time-dependent bactericidal activity; very long PAE for Gram-positive organisms PD Target: AUC0-24/MIC Goal AUC0-24/MIC ≅ 400-600 Prolonged, elevated AUC0-24/MIC ≥ 600-700 mg*h/L is a risk factor for nephrotoxicity Dosing is patient-specific and achieved through TDM using Bayesian programs

Answer 47

concentration dependent predictive PK/PD parameter: peak/MIC, AUC/MIC cidal

Answer 48

time-dependent predictive PK/PD parameter: T>MIC cidal

Answer 49

concentration-dependent predictive PK/PD parameter: AUC/MIC, peak/MIC cidal

Answer 50

concentration dependent predictive PK/PD parameter: AUC0-24/MIC cidal

Answer 51

time dependent predictive PK/PD parameter: AUC0-24/MIC cidal (slowly)