Rybakov ID 2 Flashcards by Reagan Smith

Normal Flora

Skin (5)

1) Diphtheroids (Corynebacterium spp.)
2) Staphlococci (S. epidermidis)
3) Streptococci
4) Cutibacterium acnes
5) Propionibacterium spp.

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Normal Flora

Oropharynx
(5)

1) Haemophilus spp.
2) Streptococci (viridans group)
3) Diptheroids
4) Neisseria spp.
5) Oral anaerobes

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Normal Flora

GI Tract
(7)

1) Bacteroides spp.
2) Enterobacterales
3) Enterococci
4) Fusobacterium spp
5) Peptostreptococcus spp.
6) Clostridium spp.
7) Lactobacillus

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Normal Flora

Genital Tract
(8)

1) Corynebacterium spp.
2) Enterobacterales
3) Lactobacillus spp.
4) Mycoplasma spp.
5) Staphylococci
6) Streptococci
7) Anaerobes
8) Candida spp.

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A) Pseudomonas aeruginosa

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Penicillin Binding Proteins (PBPs)

Enzymes vital for cell wall ___ , cell shape, and ___ integrity
- transpeptidases
- carboxypeptidases
- endopeptidases

Differ from one bacterial species to another

Binding to PBPs ___ , ___ , ___ and __ result in bactericidal effect

___ most important PBP
- catalyzes the final ___ in the peptidoglycan structure

synthesis
structural
1A, 1B, 2, and 3
transpeptidase
cross linking

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Bacterial Structure Summary

cytoplasmic membrane
- acts as a ___ barrier
- Certain drugs must pass through to reach target sit

selective

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Bacterial Structure Summary

Peptidoglycan Layer (cell wall)
- permeability barrier for ___ molecules
- ___ : proteins essential for cell wall synthesis

large
PBPs

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Bacterial Structure Summary

Outer Membrane (Gram-negative)
- ___ : mediator of immune response and sepsis
- Porins: ___ channels the permit diffusion of essential nutrients and small hydrophilic molecules

Lipopolysaccharides (LPS)
hydrophilic

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Bacterial Structure Summary

Periplasmic Space
- Compartment between cell ___ and cell ___ (Gram-positive) or between cell membrane and outer membrane (Gram-negative)
- Vital for bacterial ___ secretion, folding, quality control; acts as reservoir for ___ factors

membrane, wall
protein, virulence

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Intrinsic vs. Acquired Resistance

intrinsic - ___ resistant to given antibiotic

Mechanisms:
- absence of ___ site
- bacterial cell ___

Examples:
- Cephalosporins vs. Enterococci
- B-lactams vs Mycoplasma

always
target
impermeability

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Intrinsic vs. Acquired Resistance

acquired - Initially ___ but
develop resistance due to some mechanism

Mechanisms:
- Mutation in bacterial DNA (spontaneously vs. selective pressure)
- Acquisition of new DNA (chromosomal or ___ )

Examples
- stable derepression of ___
- Acquisition of ___ gene in GNRs

susceptible
plasmid
AmpC
KPC

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Acquired Resistance Definitions

Plasmid
- Self- ___ , extrachromosomal DNA
- ___ between organisms
- One plasmid can encode resistance ___ antibiotics

replicating
transferable
multiple

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Acquired Resistance Definitions

Transposons
- “ ___ genes”
- Genetic elements capable of translocating from one location to
another
- Move from ___ to ___ or vice versa
- Single transposon may encode ___ resistance determinants

jumping
plasmid, chromosome
multiple

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Acquired Resistance Definitions

Phages
- ___ that can transfer DNA from organism to organism

viruses

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Acquired Resistance Definitions

Conjugation
- bacteria ___ (pili)
- most ___
- DNA shared via mobile genetic elements (MGE), such as plasmids or transposons

sex
common

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Acquired Resistance Definitions

Transduction
- transfer of genes between bacteria by ___

bacteriophages (viruses)

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Acquired Resistance Definitions

Transformation
- Transfer or uptake of “ ___ ” DNA
from the environment
- DNA is integrated into host DNA

free floating

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B) Gram-positive have a thick cell wall; Gram-negative have a thin cell wall

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Enzymatic Inactivation: β-lactamase

Enzymes that ___ beta-lactam ring by splitting ___ bond
- Inactivates drugs

Two classification systems:
- Ambler class: classified according to amino-acid structure (Class A-D)
- Bush-Jacoby-Medeiros: according to functional characteristics

Two types:
- ___ beta-lactamases: residue at active site
- Metallo-beta-lactamases (MBL): ___ residue at active site

hydrolyze, amide
serine
zinc

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β-lactamase: Ambler Classification A

___-spectrum β-lactamases
Characteristics
- Hydrolyze penicillin; produced primarily by Enterobacterales

Enzyme Examples
- Staphylococcal penicillinase; TEM-1; SHV-1

Narrow

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β-lactamase: Ambler Classification A

___ -spectrum β-lactamases (ESBL)
Characteristics
- Hydrolyze narrow & extended spectrum-β-lactam antibiotics

Enzyme Examples
-___ , SHV-2, TEM-3

extended
CTX-M-15

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β-lactamase: Ambler Classification A

serine carbapenemase
Characteristics
- hydrolyze ___

Enzyme Examples
- ___ , ___ , ___ ; IMI-1; SME-1

carbapenems
KPC-1, KPC-2, KPC-3

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β-lactamase: Ambler Classification B

Metallo-β-lactamases
Characteristics: Hydrolyze ___

Enzyme Examples: ___ , VIM-1, IMP-1

carbapenems
NDM-1

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# β-lactamase: Ambler Classification C Cephalosporinases Characteristics - Inducible Enzyme Examples: - ___

- AMP-C

# β-lactamase: Ambler Classification D OXA-type Characteristics - Hydrolyze oxacillin, oxyimino β-lactams, and carbapenems Enzyme Examples: - ___

- OXA-48

# Ambler Class A: ESBLs Plasmid-mediated enzymes that hydrolyze most ___ , ___ , and ___ - Do not inactivate non-beta-lactam agents - often harbor additional resistance genes ___ enzyme most common - **Most prevalent in ___ , ___ , and ___** - Ceftriaxone non-susceptibility (Ceftriaxone MIC≥2) often used as proxy for ESBL production Treatment of choice: ___ (meropenem, imipenem, doripenem, ertapenem) - Merino Trial - Non-β-lactam antibiotics are an option depending on infection source & susceptibility ◦ ___ an option for urinary source only | ESBL = Extended-spectrum β-lactamases

- penicillins, cephalosporins, monobactams - E. coli, K. pneumoniae/oxytoca, P. mirabilis - carbapenems - Piperacillin/tazobactam

# Ambler Class A: Carbapenemase Most frequent cause of of Carbapenem-Resistant ___ (CRE) in the US - Resistance to whole ___ class ___ ___ carbapenemase (KPC) - Plasmid-mediated enzyme; KPC- __ & KPC- __ most common variants - Found in (6): ___ , ___ , ___ , ___ , ___ , and ___ Treatment options: - β-lactam: ___ /avibactam, ___ /vaborbactam, ___ /cilastatin/relebactam - Non β-lactam: Plazomicin, eravacycline, omadacycline

- Enterobacterales - beta-lactam - Klebsiella pneumonia - 2, 3 - K. pneumoniae, K. oxytoca, E.coli, E. cloacae, E. aerogenes, P. mirabilis - ceftazidime, meropenem, imipenem

# Ambler Class B: Metallo-β-lactamases resistance to all β-lactams except ___ (aztreonam) - Harbor additional antibiotic resistance genes to other antimicrobial classes Examples: ___ (NDM), Verona integron-encoded MBL (VIM), Imipenem hydrolyzing MBL (IMP) - Present in P. aeruginosa, Acinetobacter spp, and Enterobacterales Treatment options: - Limited! - Not inhibited by any current β-lactamase inhibitors - ___ ; ___ + ceftazidime/avibactam

- monobactams - New Delhi MBL - Cefiderocol, aztreonam

# Ambler Class D: OXA-Type Large ___ group often accompanied by other beta-lactamase classes (e.g., ___ of ESBLs and AmpC) - Primarily found in ___ , ___ and some Enterobacterales, such as ___ Treatment options: - Extremely limited - ___ - ___ /durlobactam

- heterogenous, co-expression - Acinetobacter baumannii, Pseudomonas aeruginosa, Klebsiella pneumonia - Cefiderocol - Sulbactam

# Carbapenem Resistance Summary - Resistance associated with loss of our “ ___ ” last line of defense - ___ resistance to other antibiotic classes - Resistance can be due to beta-lactamase vs. non-beta-lactamase causes (porin channels, efflux pumps) - Carbapenem-resistant Enterobacterales (CRE) does not mean ___ are present

- safest - cross - carbapenemases

B) ESBL A) meropenem

# Ambler Class C: AmpC Three different mechanisms: 1) ___ via ___ encoded AmpC genes 2) Non-inducible chromosomal resistance via mutations (rare) 3) Plasmid-mediated resistance Not inhibited by older β-lactamase inhibitors ( ___ acid, tazobactam, sulbactam) - Inhibited by newer β-lactamase inhibitors: ___ , vaborbactam, relebactam Found in HECK-Yes Ma'aM (8) - Referred to as AmpC or inducible organisms

1) inducible, chromosomally - clavulanic, avibactam - Hafnia alvei, Enterobacter cloacae, Citrobacter freundii, Klebsiella aerogenes, Yersinia enterocolitica, Serratia marcescens, Morganella morganii, Aeromonas hydrophila

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

- elevation - repressed, derepressed, beta-lactamase - repressed - mutation, derepressed, high

# AmpC Inducers High Susceptibility to AmpC hydrolysis - Strong Inducers (4) 1) Penicillin G 2) ___ 3) 1st gen cephalosporins ( ___ ) 4) Cefoxitin

- ampicillin - cefazolin

# AmpC Inducers High Susceptibility to AmpC hydrolysis - Weak Inducers (4) 1) 2nd gen cephalosporins 2) 3rd gen cephalosporins ( ___ ) 3) piperacillin/tazobactam 4) aztreonam

ceftriaxone

# AmpC Inducers Low Susceptibility to AmpC hydrolysis - Strong Inducers 1) carbapenems (3)

- imipenem - meropenem - ertapenem

# AmpC Inducers Low Susceptibility to AmpC hydrolysis - Weak Inducers (1)

- cefepime

# Selection and Treatment of Stably Derepressed Mutants Occurs in ~20-40% of cases treated with ___ gen cephalosporins - Organism will initially test susceptible, then subsequently test as resistant Treatment: ◦ ___ (1 st -line) ◦ Carbapenems ◦ Non-β-lactams (Fluoroquinolones, trimethoprim/sulfamethoxazole, tetracyclines)

- 3rd - cefepime

C) E. cloacae harbors an AmpC gene and this was induced with ceftriaxone treatment B) switch to cefepime

# Enzymatic Inactivation: Aminoglycoside-Modifying Enzymes Most common method of aminoglycoside resistance 3 mechanisms: - ___ - Nucleotidylation - Phosphorylation Modify aminoglycoside structure by transferring the indicated chemical group to a specific side chain = impairs cellular ___ and/or binding to ___ Nomenclature based on chemical group transferred and site of transfer - EX: AAC6’à aminoglycoside acetyltransferase (AAC) a the 6’ site = AAC6’-APH2’ - Bifunctional enzyme ___ and ___ of aminoglycoside - Seen in Enterococci: high level of ___ resistance

- acetylation - uptake, ribosome - acetylation, phosphorylatio n - gentamicin

# Altered Target Site: Cell Wall Precursor **Mechanism of ___ resistance in Enterococci species** - Vancomycin binds to ___ - ___ - ___ - ___ terminus of peptidoglycan precursors to inhibit ___ synthesis - Resistance alters D-Ala-D-Ala to D-Ala-D- ___ or D-Ala-D- ___ - Mediated by ___ or ___ gene (most common) - Produces vancomycin-resistant ___ (VRE) Treatment: - ___ or ___

- vancomycin - D-Alanine-D-Alanine, cell wall - Lac, Ser - VanA, VanB - enterococcus - Daptomycin, linezolid

# Altered Target Site: Penicillin Binding Proteins (PBPs) Alterations in PBPs leads to β-lactam resistance - **Due to ___ affinity of PBPs for antibiotic or change in amount of PBP produced by bacteria** - Addition of β-lactamase inhibitor is ___ in restoring activity of β-lactam antibiotic Methicillin-resistant Staphylococcus aureus (MRSA) - Resistance due to expression of ___ gene (mecA + = PBP2A + = MRSA) - Encodes for ___ : low affinity for beta-lactam antibiotics leads to resistance to β-lactam class with 2 exceptions - Treatment: Ceftaroline, Ceftobiprole; vancomycin, daptomycin, linezolid **Streptococcus pneumoniae** - Alteration in PBP confers ___ and ___ resistance

- decreased - ineffective - mecA - PBP2A - PCN, cephalosporin

# Other Altered Target Sites Ribosomal target - Responsible for macrolide resistance in ___ - ___ gene: cross resistance with clindamycin - Aminoglycoside resistance in Gram negatives - Clindamycin resistance DNA gyrase/topoisomerase IV - Responsible for ___ (ciprofloxacin, levofloxacin) resistance in Gram-negative and S. pneumoniae

- S. pneumoniae - ermB - fluoroquinolone

# Efflux Pumps & Porin Channels Efflux pumps 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 ___ antibiotics** Porin channels are ___ diffusion channels - Rate of antibiotic diffusion depends on porin & antibiotic physiochemical characteristics - ___ ___ antibiotics pass easier - Mutations result in ___ of specific porins and leads to antibiotic resistance - Most commonly seen with ___ and carbapenem-resistant ___

- P. aeruginosa - macrolide - hydrophilic - small hydrophilic - loss - Enterobacterales - P. aeruginosa

A) mecA

# Summary of Resistance Mechanisms by Drug Class Beta-lactams example drugs (4) Resistance Mechanisms - ___ - altered target site - efflux - porin channels

1) Penicillin 2) Cephalosporin 3) Carbapenem 4) Monobactam - B-lactamases

# Summary of Resistance Mechanisms by Drug Class Aminoglycosides Example drugs (3) Resistance Mechanisms - ___ - ___ - efflux

1) gentamicin 2) tobramycin 3) amikacin - AME - altered target site

# Summary of Resistance Mechanisms by Drug Class Glycopeptides Example drug: ___ Resistance Mechanisms - altered ___ precursors - thickened peptidoglycan structure

- vancomysin - cell wall

# Summary of Resistance Mechanisms by Drug Class Lipopeptides Example Drug: ___ Resistance Mechanisms - Altered ___ site - thickened ___ structure

- Daptomycin - target - peptidoglycan

# Summary of Resistance Mechanisms by Drug Class Tetracyclines Example Drugs (2) Resistance Mechanism - Altered target site - ___

- doxycycline, minocycline - efflux

# Summary of Resistance Mechanisms by Drug Class Glycycycline Example Drug: ___ Resistance Mechanisms: - altered taregt site - ___

- Tigecycline - efflux

Macrolides Example Drugs (3) Resistance Mechanisms - altered ___ site - efflux

1) Azithromycin 2) Erythromycin 3) Clarithromycin - target

# Summary of Resistance Mechanisms by Drug Class Lincosamides Example Drugs: ___ Resistance Mechanisms - altered ___ site - efflux

- Clindamycin - target

# Summary of Resistance Mechanisms by Drug Class Oxazolidinones Example Drugs (2) Resistance Mechanisms - altered ___ site - efflux

1) linezolid 2) tedizolid - target

# Summary of Resistance Mechanisms by Drug Class Fluoroquinolones Example Drugs (3) Resistance Mechanisms - altered ___ site - efflux

1) Ciprofloxacin 2) Levofloxacin 3) Moxifloxacin - target

# Summary of Resistance Mechanisms by Drug Class Pyrimidines/sulfonamides Example Drugs: ___ / ___ Resistance Mechanisms: - altered ___ site - efflux

- Trimethoprim/sulfamethoxazole - target

# Summary of Resistance Mechanisms by Drug Class Rifamycins Example Drugs: ___ Resistance Mechanisms - __ - __ - altered ___ site - efflux

- rifampin - ADP-ribosylations - target

# Summary of Resistance Mechanisms by Drug Class Catonic peptides Example drugs (2) Resistance Mechanisms: - altered ___ site - efflux

1) colistin 2) Polymyxin B - target

# definitions Bacteriostatic

Inhibit bacterial replication without killing the organism by inhibiting protein synthesis

# definitions Bactericidal

Killing of the organism by acting on areas such as the cell wall, cell membrane, bacterial DNA, etc

# definitions PAE (post antibiotic effect)

Continued growth inhibition for a variable period after concentration at site of infection has decreased below MIC

# PK/PD Indices 3 main indices

1) Cmax/MIC 2) AUC/MIC 3) fT>MIC

# Concentration-Dependent Exert effect when concentrations well above organism’s MIC - ↑ C max/MIC= greater killing; correlates with increased ___ - Some agents, such as fluoroquinolones and aminoglycosides exhibit ___ Fluoroquinolones (Levofloxacin, Ciprofloxacin) - Concentration-dependent bactericidal activity: ___ / ___ Aminoglycosides (Gentamicin, Tobramycin, Amikacin) - Concentration-dependent bactericidal activity: ___ / ___ - Some new data suggesting AUC/MIC as a predictor Optimal dosing achieved through TDM and use of high dose extended interval

- AUC - PAE - fAUC 0-24/MIC - C max/MIC

# Time-Dependent All ___ antibiotics (penicillin, cephalosporin, carbapenem, monobactam) - **Time that free drug concentrations remain above ___ 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 ___ - Time-dependent bactericidal activity - Little to no ___

- β-lactam - MIC - bactericidal - PAE

# Beta-lactam Dosing Optimization 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 - ___ dose, same interval (1g Q8h vs. 2g q8h) - Same dose, ___ interval (1g Q12h vs. 1g Q6h) - Continuous infusion ( ___ issues; need dedicated IV line) - Prolonged infusions (infuse dose over 3-4 hours, provides longer ___ > ___ than traditional infusions)

- increase - shorter - stability - T > MIC

# AUC/MIC Dependent (Vancomycin) Time-dependent bactericidal activity; very long ___ for Gram-positive organisms - PD Target: ___ / ___ - Goal AUC0-24/MIC ≅ 400-600 - assumes organism AUC of 1 mcg/mL - Prolonged, elevated AUC0-24/MIC ≥ 600-700 mg*h/L is a risk factor for ___ - Dosing is patient-specific and achieved through TDM using Bayesian programs

- PAE - AUC0-24 /MIC - nephrotoxicity

A) Time-dependent antibiotic; fT>MIC 40% of the dosing interval

# Summary of PK/PD Aminoglycosides Bactericidal Pattern - ___ dependent Predictive PK/PD Parameter(s) - ___ / ___ - ___ / ___ Cidal or Static

- concentration - Peak/MIC; AUC/MIC - cidal

# Summary of PK/PD β-lactams Bactericidal Pattern - ___ dependent Predictive PK/PD Parameter - ___ Cidal or Static

- time - T>MIC - cidal

# Summary of PK/PD Daptomycin Bactericidal Pattern - ___ dependent Predictive PK/PD Parameter - ___ - ___ Cidal or Static

- concentration - AUC/MIC - Peak/MIC - cidal

# Summary of PK/PD Fluoroquinolones Bactericidal Pattern - ___ dependent Predictive PK/PD Parameter - ___ Cidal or Static

- concentration - AUC 0-24/MIC - cidal

# Summary of PK/PD Vancomycin Bactericidal Pattern - ___ dependent Predictive PK/PD Parameter Cidal or Static

- time - AUC 0-24/MIC - cidal (slowly)