Antibiotic Agents Targeting Bacterial Cell Wall Synthesis Flashcards by Joel Glotfelty

Clavulanic acid, tazobactam, and avibactam are all

b-lactamase inhibitors

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Cefazolin (1stgen), cefuroxime axetil (2ndgen), ceftazidime (3rdgen), cefepime (4thgen), and ceftolozane (the latest) are all?

Cephalosporins

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Ceftaroline is a

Cephalosporin for MRSA

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Aztreonam is a

Monobactam

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Imipenem is a

Carbapenem

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Vancomycin, oritavancin, and dalbavancin are classified as

Glycopeptides

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Daptomycin (pore former) and polymyxins (membrane disruptors) are examples of

Lipopeptides

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Fosfomycin, bacitracin, and D-cycloserine are inhibitors of

Peptidoglycan precursors

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Life-threatening infections require the immediate use of broad-spectrum agents or

Combination therapy

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A microorganism is said to be resistant to a drug if therapeutic levels of the drug at a particular site cannot be

Safely or effectively achieved

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Exposure to harmful agents such as antibiotics increases the selective pressure to maintain

Acquired resistance

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Many drugs work selectively against Gram(+) bacteria. Fewer work selectively against Gram(-) bacteria. Drugs that work against both classes of bacteria are said to be

Broad spectrum

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A drug whose selectivity is broadened by chemical modification is said to have an

Extended spectrum

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The outer membrane of Gram(-) bacteria is relatively

Impermeable

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Cell wall agents block proper assembly of the

Peptidoglycan layer

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Join the sugars that make polysaccharide chains

Transglycolase enzymes

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Join the sugar-linked peptides to x-link polysaccharide chains

Transpeptidase enzymes

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Mimics D-Ala-D-Ala, the last two amino acids of the peptide-bridge precursor

Penicillin

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Similar to transpeptidases. However, they use H2O to hydrolyze serine-lactam linkage

Serine B-lactamases

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A distinct class that hydrolyze lactams by a different mechanism

Metallo B-lactamases

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Possess no antibacterial activity. They are combined with blactam antibiotics to extend their half-lives

B-lactamase inhibitors

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These inhibitors bind b-lactamases covalently and inactivate irreversibly

Beta-lctamase inhibitors

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Initially, b-lactamases were encoded by chromosomal genes of some bacteria. Amplification of the genes led to increased

Activity

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Later, lactamases were found on plasmids that could transfer from

Organism to organism

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Most active against plasmid encoded b-lactamases in staphylococci, H. influenza, N. gonorrhoeae, salmonella, shigella, E. coli, K. pneumoniae

Clavulanic Acid

Least active against chromosomally-encoded b-lactamases in enterobacter, citrobacter, serratia, pseudomonas

Clavulanic acid

Serine β-lactamases come in which three classes

A, C, and D

Traditional B-lactamase inhibitors work primarily on

Class A enzymes

A broader spectrum β-lactamases inhibitor that works on class A and C enzymes, as well as some D enzymes.

Avibactam

The inhibitor is coformulated with 3rd generation cephalosporin, ceftazidime -Note: The inhibitor does not contain a β-lactam core

Avibactam

How many classes of penicillins are there, defined by core structure plus substituents

Common penicillins, anti-staphylococcal penicillins, and extended-spectrum penicillins

Acid labile. b-lactamase susceptible. Suitable for Gram(+), Gram(-) cocciand non blactamase-producing anaerobes

Common penicillins

Acid stable. b-lactamase resistant. Suitable for b-lactamase producing strains of staph, as well as penicillin-susceptible strains of streptococci and pneumonococci

Anti-staphylococcal penicillins

Not suitable for enterococci, anaerobic bacteria, and Gram(-) cocciand rods

Anti-staphylococcal penicillins

Acid stable. Greater activity against Gram(-) because of their ability to penetrate outer membrane. Suitable for UTIs, sinusitis, otitis, lower respiratory tract infections

Extended-spectrum penicillins

Extended-spectrum penicillins are inactivated by

Lactamases

Inactivated by lactamases. Thus, available in combination with b-lactamase inhibitors (eg. amoxicillin + clavulanate = Augmentin)

Extended-spectrum penicillins

Routes of administration-oral, IV and IM (if combined with anesthetic). When taken orally, ingest one hour before or after meal to avoid binding to food proteins

Penicillins

Penicillins are eliminated by

Rapid active secretion

80% of a dose of penicillin can be cleared in

3-4 hours after administration

Competitively inhibits penicillin secretion. Use it to increase steady state level and t1/2

Probenecid

Side effects can include diarrhea, nausea, rash, urticaria, and/or superinfectionwith other microbes (e.g. candidiasis)

Penicillins

If a patient is allergic to penicillin, we an substitute with

Cephalosporins

Penicillin resistance can occur by upregulation of chromosomally-encoded

B-lactamases

Penicillin resistance can also occur by acquisition of B-lactamaes by horizontal gene transfer from other

Bacteria

Mutation of the primary penicillin binding proteins (transpeptidases) such that penicillin binding affinity is reduced

MRSA

Broader spectrum due to increased resistance to b-lactamases

Cephalosporins

Not active against enterococci, L.monocytogenesor E. coliand Klebsiellastrains that express extended-spectrum b-lactamases

Cephalosporins

1st generation cephalosporins are broad spectrum, but are better for

Gram (+)

Restricted to surgical prophylaxis. Does not penetrate CNS

Cefazolin

In general they extend the coverage of Gram(-) bacteria over 1st generation drugs -Heterogeneous class with individual specificities

2nd generation cephalosporins

Extend Gram(-) activity at the expense of Gram(+) activity

3rd generation cephalosporins

Some cross blood-brain barrier. Effective against inducible blactamase-production but not constitutive b-lactamase-producing strains

3rd generation cephalosporins

Cetftazidime+ β-lactamase inhibitor (avibactam)

Avycaz

More resistant to chromosomal b-lactamases

4th generation cephalosporins

Increased activity toward Gram(+) and Gram(-) species. True broad spectrum drug. Penetrates the CNS

4th generation cephalosporins

Route of administration -Some oral, some IV

Cephalosporins

Used for sinusitis, otitis and lower respiratory tract infections. -Fourth generation appropriate for MRSA

Cephalosporins

Cephalosporins may elicit

Hypersensitivity reactions

A 5th generation cephalosporin for treatment of Gram(-) bacteria that have become resistant to other drugs, particularly pseudomonas infections

Ceftolozane

Used for complicated UTIs, and in combination to with metronidazole for complicated intra-abdominal infections

Ceftolozane

A β-lactamase inhibitor that extends half-life of the cephalosporin

Tazobactam

Approved in 2010 for use against MRSA. -Drug has high affinity toward the unique transpeptidase commonly encoded by MRSA

Ceftaroline

Ceftaroline, like other later generation cephalosporins, works on both

Gram (+) and Gram (-) bacteria

The most common side effects of ceftaroline are

Diarrhea, nusea, and rash

Monocyclic core. -Relatively resistant to b-lactamases

Monobactams

Monobactams are active against

Gram (-) rods

Monobactams have no activity against

Gram (+) rods

The drug does not bind transpeptidases of Gram(+) or anerobic bacteria

Monobactams

Broad spectrum antibiotics with good activity against many Gram(-) rods (including P aeruginosa), Gram(+) bacteria and anaerobes

Carbapenems

Resistant against the actions of serine b-lactamases but not metallo b-lactamases

Carbapenems

Inactivated by dehydropeptidases in renal tubules

Imipenem

An inhibitor of renal dehydropeptidase increases t1/2

Cilastatin

The carbapenems are well distributed, including penetration of CNS. All are cleared renally. Dose (by IV) must be adjusted in patients with

Renal insufficiency

Carbapenems may show cross-reactivity in patients with

Penicillin allergies

Glycopeptide isolated from soil bacterium. -Active against Gram(+) bacteria, especially staphylococci

Vancomycin

Bactericidal for actively growing cells -Binds the cell wall rather than enzymes used to make it

Vancomycin

Vancomycin binds tightly to D-Ala-D-Ala of nascent peptidoglycan pentapeptide. The binding interferes with

Transglycosylation and transpeptidation reactions

Vancomycin resistance in enterococci arises from a switch in the peptidoglycan pentapeptide from D-Ala-D-Ala to

D-Ala-D-Lac

Common indications: methicillin-resistant endocarditis or sepsis

Vancomycin

A better choice than vancomycin if the strain is methicillin sensitive

Penicillin

Routes of administration–usually IV, oral for enterocolitis and diarrhea caused by C. dificile

Vancomycin

Often used with aminoglycosides or gentamicin for treatment of enterococcal and other infections

Vancomycin

Semisynthetic lipoglycopeptide derivative of teicoplanin -Effective for skin infections by MR gram-positive bacteria

Dalbavancin

Semisynthetic glycopeptide derived from vancomycin -Comparable efficacy to vancomycin

Oritavancin

Cyclic lipopeptide isolated from soil bacteria

Daptomycin

Forms pores in membrane that allow K+ loss without cell rupture. No release of toxins

Daptomycin

Based on evolutionarily conserved antimicrobial host defense peptides mimetics. -Thought to form pores, like daptomycin

Brilacidin

Brilacidin has potent broad-spectrum activity against Gram-positive and Gram-negative bacteria, including

MRSA

A class of lipopeptides that bind outer membrane of Gram(-) bacteria

Polymyxins

Polymyxins ultimately leads to the permeability of both the

Inner and outer membranes

Binds a lipopolysaccharide molecule specific to outer membranes of Gram(-) bacteria. There is little activity against Gram(+) bacteria

Polymyxins

Drug inhibits first committed step in cell wall synthesis: conversion of NAG-UDP to NAM-UDP

Fosfomycin

The drug binds covalently to the active site cysteine of the MurA enzyme

Fosfomycin

Naturally resistant to fosfomycin

MurA of TB

Fosfomycin is used for uncomplicated

UTIs

Cyclic polypeptide active against Gram(+) organisms -Inhibits lipid phosphatase that dephosphorylates lipid carrier of peptidoglycan subunits

Bacitracin

Only used topically because too nephrotoxic

Bacitracin

Drug competitively inhibits alanine racemase and D-alanine ligase

D-cycloserine

Second line drug with serious side effects: Dose related CNS toxicity (headaches, tremors, convulsions, psychosis)

D-cycloserine

Antibiotic Agents Targeting Bacterial Cell Wall Synthesis Flashcards

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