DR. MABANAG - BETA LACTAMS + OTHER CELL WALL & MEMBRANE ACTIVE ANTIBIOTICS Flashcards
4 Major categories of Bacterial targets
- Cell Wall
● Beta lactams, Vancomycin - Outer cell membrane
● Polymyxins - Nucleic acid
● Fluoroquinolone, Trimethoprim - Ribosomes
● Aminoglycosides, Spectinomycin, Tetracyclines, Macrolides, Chloramphenicol, Linezolid
○ Buy AT 30
- Aminoglycoside
- Tetracycline
○ SCEL at 50
- Streptogramins
- Chloramphenicol, Clindamycin
- Erythromycin (Macrolides)
- Linezolid
● There are two subfamilies:
○ Those that attack 50S Subunit
○ Attack 30S Subunit
● Antibiotics also attack Nucleic acid synthesis, like in
folate synthesis
C-S-T
cotrimoxazole
sulfonamides
trimethoprim
attack the DNA gyrase.
QUINOLONES
attacks the RNA polymerase.
RIFAMPIN
______bactericidal by inhibiting bacterial cell wall synthesis leading to loss of cell wall integrity and eventually cell lysis
BETA LACTAMS
most complex subclasses of beta-lactams
P-C
PENICILLIN
CEPHALOSPORINS
All beta-lactams inhibit synthesis of the ___________found on the bacterial cell wall
PEPTIDOGLYCAN LAYER
● A heteropolymer component of bacterial cell wall that provides rigid mechanical stability
● It maintains bacterial cell shape and integrity and prevents bacterial cell lysis from high osmotic pressure.
PEPTIDOGLYCAN LAYER
PEPTIDOGLYCAN LAYER
Composed of alternating chains of:
?
?
○ N-acetylglucosamine (NAG)
○ N-acetylmuramic acid (NAM)
● They are pentaglycine cross-linked by peptide
chains
● If peptidoglycan is weakened or synthesis is inhibited, cell lysis occurs or the cell would not be able to replicate.
PEPTIDOGLYCAN LAYER COMPOSITION
OLD BETA LACTAMS ARE MORE ACTIVE AGAINST GRAM + THAN GRAM-
○ Gram-positive = Very thick peptidoglycan layer
○ Gram-negative = Thin peptidoglycan layer
inhibit synthesis of the peptidoglycan layer by binding to and inhibiting the action of TRANSPEPTIDASE involved in the cross-linking of peptidoglycan chains.
ALL BETA-LACTAMS
○ Involved in the cross-linking of
peptidoglycan chains
○ It represents one of the multiple types of
penicillin-binding proteins (PBPs).
○ Inhibitory action on the transpeptidase
enzyme has a bactericidal effect as the impaired peptidoglycan synthesis leads to loss of bacterial shape and integrity thus leading to cell lysis and cell death.
TRANSPEPTIDASE
- Porin Mutations (e.g., Klebsiella spp.)
● Decreases entry of beta-lactams. - Action of B-Lactamases
● Degradation of antibiotics once inside the cell.
● Combat against antibiotics. - Efflux Pumps (e.g., P. aeruginosa)
● Removal of antibiotic once inside the cell. - PBP mutations
● Not allowing binding of beta-lactam.
● So that the drug cannot attach.
Major mechanisms of beta-lactam resistance:
Resistance for beta-lactams in G(-) bacilli are usually due to
BETA LACTAMASE PRODUCTION
encode plasmids (which are passed from bacterium to bacterium by horizontal transfer) or encoded by the bacterial chromosome itself.
Beta-lactamases (anti-beta lactam enzymes)
BETA LACTAMASE:
Inactivate penicillins
Penicillinases
BETA LACTAMASE:
- Inactivate most beta-lactams except carbapenems.
- Mostly found in E. coli and Klebsiella spp.
○ Extended-spectrum beta-lactamases (ESBLs)
BETA LACTAMASES:
- Inactivate carbapenems
- Used as treatment of last resort for
multi-drug resistant G(-) infections.
Carbapenemases
more commonly observed among G(+) pathogens.
● Confers resistance to all beta-lactam antibiotics with one exception, Ceftaroline which is a newer cephalosporin.
ALTERED PENICILLIN BINDING PROTEINS (PBPs)
one of the most complex subclasses of beta-lactam antibiotics.
● All have the same basic structure: the 6-aminopenicillanic acid nucleus - a thiazolidine ring attached to a beta-lactam ring that carries a secondary amino-group.
PENICILLINS
Natural Penicillins (Penicillin Sensitive)
Have the greatest activity against gram-positive (+) organisms, gram-negative (-) cocci, and non-beta-lactamase-prod ucing anaerobes
Penicillin G
Penicillin V
Antistaphylococcal Penicillins (Penicillinase- Resistant)
Resistant to staphylococcal beta-lactamases
Cloxacillin
Oxacillin
Antistaphylococcal Penicillins (Penicillinase- Resistant)
Only active against staphylococcus and staphylococci but not against other gram-negative (-) rods.
Nafcillin
Methicillin (Con-MD)
Extended-Spectrum Penicillins
Aminopenicillin
Relatively susceptible to hydrolysis by beta-lactamases
Aminopenicillins:
- Ampicillin
- Amoxicillin
Extended-Spectrum Penicillins
antipseudomonal penicillins
Most commonly formulated and administered in combinations with beta-lactamases inhibitors.
Antipseudomonal: - Carbenicillin
- Ticarcillin
- Piperacillin
used in the ICU, there are aggressive pathogens and use stronger antibiotics.
ANTIPSEUDOMONALS
- Carbenicillin
- Ticarcillin
- Piperacillin
Anti-staphylococcal PCNs
Resistant against β-lactamases
Only active vs Staphylococci and Streptococci
Penicillin-Resistant PCNs
Cloxacillin
Oxacillin
Dicloxacillin
Nafcillin
Methicillin
● Retain the same antibacterial activity of natural PCNs, w/ added activity vs G(-) rods.
● Retain susceptibility to hydrolysis by β-lactamases
Extended-SpectrumPCNs
○ Aminopenicillins: Ampicillin, Amoxicillin
○ Antipseudomonal PCNs: Carbenicillin,
Ticarcillin, Piperacillin
Give oral penicillins, except_________, in between meals. Should be administered at least 1-2 hours before or after a meal.
amoxicillin
PCNs are rapidly excreted by the kidneys via
1.
2.
- TUBULAR SECRETION
- GLOMERULAR FILTRATION
an anti-staphylococcal PCN, is primarily cleared by biliary excretion.
NAFCILLIN
● Drug of choice (DOC) for infections caused by:
○ Streptococci
‐ E.g. “Strep throat” (Streptococcus
pyogenes) ○ Meningococci
‐ E.g. Meningococcemia (Neisseria meningococci)
○ Penicillin-susceptible Pneumococci
‐ E.g. Pneumonia (Streptococcus pneumoniae)
○ Non-β-lactamase-producing Staphylococci
○ Treponema pallidum
‐ E.g. Syphilis
‐ In the 1950s, it was also the first line of treatment for syphilis.
○ Actinomyces
○ Clostridium sp.
PENICILLINASE-SENSITIVE PENICILLINS (NATURAL PCNs)
are considered DOCs for serious staphylococcal infections such as endocarditis (infection of the heart muscles or valves)
-OXACILLIN
-NAFCILLIN
-PNEUMOCOCCI
-TX BACTERIAL SINUSITIS,OTITIS AND LRTIs
-Shigella, Listeria monocytogenes, E. coli, Salmonella, and Haemophilus influenzae
-treatment of Gram(-) bacilli infections caused by Pseudomonas aeruginosa and Klebsiella pneumoniae.
EXTENDED-SPECTRUM PENICILLINS (AMINOPENICILLINS [Ampicillin & Amoxicillin], ANTIPSEUDOMONAL PCNs)
PCN
ADVERSE EFFECT
MC= ALLERGY / HYPERSENSITIVITY
*ANAPHYLACTIC SHOCK
○ PCN and their breakdown products of alkaline hydrolysis act as haptens after covalent reaction with proteins → PENICILLOIC ACID
if the patient is allergic to one of the penicillins, especially if there is severe reaction, it should be presumed that all penicillins are contraindicated and the entire group should be avoided.
Complete (Absolute) Cross-Allergenicity
if allergic to penicillin, patients can be given cephalosporin. They are both β-lactams, but not exactly penicillin formulations. However, a better choice would be not to use any β-lactam antibiotics.
‐ If a patient is allergic, it is safer to give non-β-lactam antibiotics.
Partial Cross-Allergenicity
Gastrointestinal disturbance (i.e. nausea, vomiting, and diarrhea)
large PO doses of PCNs
Pseudomembranous colitis
AMPICILLIN
Myoclonic jerks and seizures
high doses of PenG
or patients with renal failure
Interstitial nephritis
Nafcillin, Methicillin
(Antistaphylococcal Penicillins;
Neutropenia
NAFCILLIN
HEPATITIS
OXACILLIN
(Antistaphylococcal Penicillin)
○ Occurs several hours after 1st injection of PCN
○ Symptoms: chills fever, headache, myalgias, arthralgias
Jarisch Herxheimer Reaction
