Rybakov ID 2 Flashcards
Normal Flora
Skin (5)
1) Diphtheroids (Corynebacterium spp.)
2) Staphlococci (S. epidermidis)
3) Streptococci
4) Cutibacterium acnes
5) Propionibacterium spp.
Normal Flora
Oropharynx
(5)
1) Haemophilus spp.
2) Streptococci (viridans group)
3) Diptheroids
4) Neisseria spp.
5) Oral anaerobes
Normal Flora
GI Tract
(7)
1) Bacteroides spp.
2) Enterobacterales
3) Enterococci
4) Fusobacterium spp
5) Peptostreptococcus spp.
6) Clostridium spp.
7) Lactobacillus
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.
A) Pseudomonas aeruginosa
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
Bacterial Structure Summary
cytoplasmic membrane
- acts as a ___ barrier
- Certain drugs must pass through to reach target sit
- selective
Bacterial Structure Summary
Peptidoglycan Layer (cell wall)
- permeability barrier for ___ molecules
- ___ : proteins essential for cell wall synthesis
- large
- PBPs
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
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
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
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
Acquired Resistance Definitions
Plasmid
- Self- ___ , extrachromosomal DNA
- ___ between organisms
- One plasmid can encode resistance ___ antibiotics
- replicating
- transferable
- multiple
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
Acquired Resistance Definitions
Phages
- ___ that can transfer DNA from organism to organism
viruses
Acquired Resistance Definitions
Conjugation
- bacteria ___ (pili)
- most ___
- DNA shared via mobile genetic elements (MGE), such as plasmids or transposons
- sex
- common
Acquired Resistance Definitions
Transduction
- transfer of genes between bacteria by ___
bacteriophages (viruses)
Acquired Resistance Definitions
Transformation
- Transfer or uptake of “ ___ ” DNA
from the environment
- DNA is integrated into host DNA
- free floating
B) Gram-positive have a thick cell wall; Gram-negative have a thin cell wall
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
β-lactamase: Ambler Classification A
___-spectrum β-lactamases
Characteristics
- Hydrolyze penicillin; produced primarily by Enterobacterales
Enzyme Examples
- Staphylococcal penicillinase; TEM-1; SHV-1
Narrow
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
β-lactamase: Ambler Classification A
serine carbapenemase
Characteristics
- hydrolyze ___
Enzyme Examples
- ___ , ___ , ___ ; IMI-1; SME-1
- carbapenems
- KPC-1, KPC-2, KPC-3
β-lactamase: Ambler Classification B
Metallo-β-lactamases
Characteristics: Hydrolyze ___
Enzyme Examples: ___ , VIM-1, IMP-1
- carbapenems
- NDM-1
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)
