Antibiotics I - Med Micro Flashcards
The role of Penicillin Binding Proteins and the Cell wall
PBPs are needed in order for cross linking and building the peptidoglycan cell wall. Act as transglycosylases and transpeptidases. Cell wal agents act on specific PBPs
transglycosylases
PBPs act as these in joining NAG and NAM
transpeptidases
PBPs act as these in the cross linking of the peptidoglycan sheets- it will cleave off the final D-ala residue for cross linking to occur
B Lactam Antibiotics AND the Classes
Are B Lactam Cell Wall Agents, because they inhibit cell wall synthesis. They consist of Penicillins, Cephalosporins, Carbapenems and Monobactams ( Aztreonam)
Pathways utilized by B lactam antibiotics into the outer membrane of gram negative bacteria
- a lipid mediated pathway for hydrophobic antibiotics 2. general diffusion porins for hydrophilic antibiotics
What are Penicillins and what do they do?
are B lactam based compounds, have a 4 membered B lactam ring and a 5 membered thiazolidine ring its fused to.
Features of the B lactam ring
- it binds to and inhibits transpeptidases (PBPs), 2. it is a substrate for B lactamases 3. it is a very unstable structure
What are Cephalosporins and what do they do?
are described in context of generations, Are structurally similar to penicillins. Have increasing activity to various gram negative bacteria. Higher generations are less susceptible to Beta lactamases
The other Inhibitors of Cell Wall Synthesis
Carbapenem and Monobactams
How do the Beta Lactam Antibiotics work?
B Lactam Antibiotics are structurally similar to the D-ala-D-ala residue so B lactam antibiotics react/bind to PBP proteins and inactivate them
How does the Bacteria FIGHT back? What’s in its arsenal?
B- lactamases, ESBLs (extended spectrum B lactamases), Amp C Beta Lactamases (IDBLs) and the Carbapenemases
What are the B Lactamases and how do they work?
Are bacterial enzymes that can inactivate the B Lactam antibiotics by hydrolyzing the B lactam bond and destroying the B Lactam ring. Are a form of resistance to the antibiotics. Can differ in their substrate profile
B Lactamase Production
May be constitutive- a constant basal level of the enzyme is produced at all times, not affected by external env’t or inducible - produced after exposure to certain antibiotics in its env’t
Activity of the B lactamase depends on
Depends on having a zinc or a serine at the active site to hydrolyze the B lactam ring
Different Classes of B lactamases
- Narrow Spectrum B Lactamases 2. Extended Spectrum Beta Lactamases (ESBLs) 3. AmpC production (IDBL) 4. Carbapenemase production (CRE)
Two ways to outsmart the Beta Lactamases
- Build a better drug resistant to the B Lactamases 2. Combine and antibiotic with an Inhibitor that resembles the Antibiotic - B Lactamases will preferentially bind irreversibly to to the Inhibitor ( Antibiotic look alike) and thus, the B Lactamases are out of the system.
Extended spectrum Beta Lactamases
Are plasmid mediated B lactamases which hydrolyze penicillins, 3rd and 4th generation cephalosporins, and aztreonam.
ESBLs are inhibited by and have no activity against
Inhibited by B lactamase inhibitors such as clavulanate, tazobactam and subactam and have no activity to the carbapenases (imipenem) or cephamycins (cefoxitin or cefotetan)
what are the most effective agents against ESBL producing Enterobacteriacae
Carbapenems ( imipenem, ertapenem, meropenem)
General Summary on Tests used to detect ESBL producing organisms
Are screening and confirmatory tests that are used for isolates of specific organisms, E.Coli, Klebsiella pneumoniae, K. oxytoca and Proteus mirabilis and are based on reduced sensitivity to indicator drugs
what are the tests to detect ESBL producers?
- double disc synergy 2. combination disk method 3. E-test
Confirmatory Tests for ESBLs do
Indirectly detect the hydrolysis of indicator drugs
How does the Double DisK Synergy test work?
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How does the Combination Disk Method work?
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penicillinase resistant penicillin and 2 examples, also what organism is resistant to these kinds of penicillins?
are antibiotics not inactivated by penicillinase or B lactamase produced by bacteria. Two examples - Methicillin and oxacillin. MRSA is resistant to these drugs.
penicillin and cephalosporins work the same way by
inhibiting the cross linking of peptidoglycan by binding to and inactivating the PBPs
a patients is allergic to Penicillin
give them Cephalosporins
1st generation cephalosporins are best at treating
gram positive bacteria like Staph/Strep
3rd and 4th generation cephalosporins are best at
being resistant to the action of many beta Lactamases. Active against most gram negative bacteria including Pseudomonas
2nd generation cephalosporins have
good activity against Haemophilus influenza
An agent that inhibits cell wall synthesis outside of the Beta Lactams
Glycopeptides (Vancomyin) - these are effective against Gram positive organisms only, the gram negatives are resistant. Act by binding to D-alanyl D-alanine residues
Inhibitors of protein synthesis
A.T.M. L.L.C –
Aminoglycosides, Tetracyclines, Macrolids, Lincosamides, Linezolid, Chloramphenicol
Carbapenems
are a class of B Lactam antibiotics, with a broad spectrum of antimicrobial activity. they are highly resistant to most B lactamases including ESBL’s .
what confers methicillin resistance in Staph Aureus
In S.aureus, methicillin resistance is conferred by the mecA gene, which encodes PBP2A, which has low affinity for B lactam antibiotics…
With MRSA, Methicillin, oxacilin, nafcillin, and Beta Lactamase inhibitors will not work.
pharmacodynamics refers to
the effects of the drug on the bacteria
pharmacokinetics refers to
how the body takes in the drug
MIC is what
the lowest antibiotic concentration that is inhibitory to 90% of all isolates.
Amp C Beta Lactamases
“cephalosporinases” these hydrolyze all beta lacatam antibiotics except carbapenems. Amp C gene is in most species except Klebsiella, E.Coli, and Protues.
Amp C gene is
present in many bacteria it is hardwired, its inducible resistance requires long term extended therapy before Amp c is produced.