Understanding Beta-Lactam Antibiotics: Part 1 Flashcards
B-lactam are bactericidal by inhibiting _________________, leading to loss of cell wall integrity and __________
bacterial cell wall synthesis; cell lysis
T/F: B-lactams are used in both inpatient and outpatient settings
T
Most commonly used class of antibiotics in the US
B-lactam
Possible ADE of B-lactams include
hypersensitivity reactions, gastrointestinal effects
Penicillinase-sensitive PCNs
PCN-G, PCN-V
Penicillinase-resistant (Anti-staphylococcal PCNs)
Methicillin, dicloxacillin, oxacillin, nafcillin
Extended-spectrum PCNs
Amoxicillin (+/- clavulanate)
Ampicillin (+/- sulbactam)
Ticarcillin (+/- clavulanate)
Piperacillin (+/- tazobactam)
Monobactams
Aztreonam
Beta-lactams also function by inhibiting the synthesis of the _______________ layer.
peptidoglycan
critical in the cross-linking of peptidoglycan chains
transpeptidase enzymes
Located in the periplasmic space between the peptidoglycan layer and the plasma membrane
Penicillin binding proteins (PBPs)
functions of the cross-linked peptidoglycan layer:
Maintains bacterial shape and integrity
Prevents cell lysis from high osmotic pressure
Peptidoglycan layer are found in both ___________ and _____________
Both gram-positive and gram negative bacteria
there is a very thick outer peptidoglycan scaffolding in gram ___________,
postivies
have thin peptidoglycan layer between the outer membrane and plasma membranes
gram negatives
If the peptidoglycan layer is weakened or its synthesis inhibited, there is ______________
bactericidal effect
Impaired peptidoglycan synthesis leads to loss of bacterial shape and integrity, then _________ occurs, making cells unable to _________. This ultimately will result to ____________
cell lysis; replicate; cell death
act as structural analogs, specifically targeting the D-ala-D-ala structure, inhibiting transpeptidase activity called transpeptidation.
Beta-lactam antibiotics
Beta-lactam antibiotics act as structural analogs, specifically targeting the ___________ structure, inhibiting transpeptidase activity called transpeptidation.
D-ala-D-ala
Before PG cross-linking, PG chains feature _________ moieties connected to 5-amino-acid peptides (ordered __________)
NAM, A-G-L-A-A
During PG cross-linking, ___________ (a type of PBP) removes the terminal A and links the 2nd A to neighboring L, thus forming a connected _________ (“-“ between A and L)
transpeptidase; latticework
After PG cross-linking, the resultant scaffold provides ______________ to the bacterial cell
structural integrity
four major mechanisms of bacterial resistance to beta-lactams:
- _____________ entry of beta-lactam into the cell via ___________ mutations
- altered target, specifically, ____________ not allowing for beta-lactam binding to their target
- _______________, as represented by beta-lactamases
- _______________ or an antibiotic once in the cell via _____________, for example, those found in ________
-decreased; porin
-PBP mutations
-degradation
-Removal; efflux pumps; P. aeruginosa
B lactamases have major mechanism in
gram-negative pathogens
May be passed from bacterium to bacterium via horizontal transfer
Plasmid-mediated B-lactamases
B lactamases can be _______ or _________-mediated ; but most are _________
plasmid- or chromosomally-mediated; plasmid-mediated
may harbor repressed AmpC β-Lactamase genes in their chromosomes which may become induced or derepressed during treatment with beta-lactams
SPACE organisms
may initially be suscpetible to beta-lactams but become resistant during beta-lactam therapy
SPACE organisms
Main types of B-lactamases:
-Penicillinases
-“Extended-spectrum B-lactamases”
-Carbapenemases
inactivate penicillins
Penicillinases
inactivate most B-lactams except for carbapenems
“Extended-spectrum B-lactamases” (ESBLs)
they include things like penicillinaces and cephalosporinases
“Extended-spectrum B-lactamases” (ESBLs)
Most commonly produced by E. coli and Klebsiella spp.
“Extended-spectrum B-lactamases” (ESBLs)
are the antibiotics of choice for ESBL highly resistant pathogens
Carbepenems
example of carbapenemases
OXA, KPC, metallo-B-lactamases
inactivate carbapenems
Carbapenemases
are the last resort for multi drug-resistant gram negative infections, unfortunately gram negatives that produce carbepenemases have recently emerged and spread globally
carbepenems
tx of gram _________ pathogens are extremely challenging as they are often multi drug resistant
negative
generally resistant to all available beta-lactams and most other antibiotic classes, with the exception of poly mix-ins which is an old class of antibiotics
Carbapenem-Resistant Enterobacteriaceae (CRE)
an old class of antibiotics previously pulled from the shelves due to its renal toxicity and neural toxicity
poly mix-ins
Carbapenem-Resistant Enterobacteriaceae (CRE) are resistant to all available beta-lactams and most of antibiotic class except for
poly mix-ins
Altered PBPs are more common in
gram-positive pathogens
clinical example of PBPs
MRSA and the SCCmec genomic island.
Altered PBPs include different enzymes such as
transpeptidases, carboxypeptidases and endopeptidases
main target of beta-lactams
Transpeptidase
T/F: Altered PBPs may be unique to a particular pathogen
T
main altered PBP in methicillin-resistant S. aureus (MRSA)
PBP2a
main altered PBP in penicillin-resistant S. pneumoniae
PBP2x
has very high affinity for PBP2a, which accounts for its unique, potent activity vs. MRSA
ceftaroline
Resistance mechanism of MRSA:
-__________________________ is a genomic island that contains the mecA gene
-mecA encodes PBP2a, whose active site does not bind B-lactams (except ______________)
Staphylococcal cassette chromosome mec (SCCmec); mecA; ceftaroline
Resistant to all B-lactams (except ceftaroline) and variable susceptibility to rifamycins, tetracyclines, lincosamides, TMP-SMX
MRSA
MRSA is reliably treated with __________, __________, ______________, although rare reports of resistance
glycosides, lipopeptides, and oxazolidinones
