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Transcript
Drugs /Agents
Inhibitors of cell wall
synthesis
Inhibitors of bacterial cell wall
biosynthesis

In principle, drugs that inhibit bacterial cell wall
synthesis will exhibit selective toxicity, because the drug
targets are unique to bacteria and are not present in
human cells.

In practice,this principle is valid, and inhibitors of cell
wall synthesis such as the B-lactams are drugs of choice
for many bacterial infections.

The availability of B-lactam drugs with distinct
antimicrobial spectra permits their use in a wide variety
of clinical setting.
Inhibitors of bacterial cell wall
biosynthesis

The B-lactam drugs are bactericidal and relatively non-toxic to
human cells. This attractive pharmacological property has led to
overuse and misuse, resulting in the emergence of drug-resistant
bacteria.

Resistance due to B-lactamase production can sometimes be
overcome by using a B-lactamase inhibitors in combination with
the B-lactam drug.

Resistance due to an alteration in the B-lactam target often
cannot be surmounted, and a different drug class must be used for
treatment.
MoA of PCN

Penicillin-binding proteins (PBPs): Targets for B-lactam drugs

Penicillin-binding proteins (PBPs = transpeptidase enzymes) differ among
bacterial species.

PBPs differ in their affinities for B-lactam drugs.
Therefore, bacteria can differ in susceptibility to B-lactam drugs because their
transpeptidase enzymes are different.


Mutation in a PBP can confer resistance to B-lactam drugs examples.
Example

Methicillin-Resistant Staph. Aureus

Penicillin-resistant Strep. Pneumoniae

All β-lactam antibiotics interfere with the synthesis of the bacterial cell wall
peptidoglycan. After attachment to penicillin-binding proteins on bacteria
(there may be seven or more types in different organisms), they inhibit the
transpeptidation enzyme that crosslinks the peptide chains attached to the
backbone of the peptidoglycan.

The final bactericidal event is the inactivation of an inhibitor of autolytic
enzymes in the cell wall, leading to lysis of the bacterium.
Enzymes that cleave B-lactam drugs

B-lactamases cleave the C-N
bond of the B-lactam ring,
inactivating the drug.

Production of B-lactamase is a
major cause of resistance.

There are many different Blactamases, and they vary in
specificity.

Development of drugs that
inactivate B-lactamse has helped
combat resistance.
B-lactam action

B-lactam drugs must:
 Penetrate outer membrane
 Escape inactivation
 Bind to target enzymes

Resistance can be due to
 Lack of membrane penetration
 Inactivation by B-lactamase
 Altered target PBPs

Semi-synthetic drugs have modification that:
 Improve penetration through porins, enhancing Gram - negative
activity.
 Decrease B-lactames susceptibility, broadening spectrum
 Alter PBP binding pattern, changing spectrum.
PENICILLINS

Side Effects:
MOA: inhibit bacterial cell wall synthesis bactericidal!

Target: PBP (cell wall transpeptidase)

 Lactam antibiotics

PCN are polar: Mostly Excreted primarily by
kidneys

Diarrhea: 5-10%

Rash: 4-10%

Fever: 4-8%

Neutropenia: 1-4%

Exceptions: Nafcillin, Oxacillin

Thrombocytopenia: 1-2%

Dose adjustment needed in renally

Hypersensitivity Rxn
insufficient patients


Tissue penetration: good

Lung, liver, kidney, muscle, bone

Most common AE and PCN
may be the most common
cause of drug allergy.
Seizures: 1%
Adverse Effects of PCN

Allergic reactions include various skin rashes, serum-sickness (rare), and
anaphylaxis (rare).

Assume cross-allergenicity among PCNs.

N&V: reflect direct irritation of the GI tract and/or alterations in bowler
flora.

In renal failure, Na+ or K+ toxicity can produce Seizures.
Natural PCNs
Agents
Pen G (PO), Pen VK, Benzathine PCN (long acting IM injection, used in
syphilis)
Coverage
GRAM +


Very little clinically relevant gram –
Strep:

Pneumo, ABCG: >60% susc.

Viridans: 30-60% susc.
Enterococcus:

Faecalis >60%

Faecium 30-60%
 PCN G: neisseria meningitidis
Anaerobes:
 Actinomyces: 30-60%
 Clostridium (not difficile): >60%
 Peptostreptococcus: >60%
Penicillinase Resistant PCNs
(Anti-Staph PCNs)
Primary Coverage
Agents
GRAM +

Methicillin

Oxacillin

Staph (MSSA & Epi): >60%
Nafcillin

Strep:



Dicloxacillin (PO)
Nafcillin, oxacillin:

Pneumo, ABCG: >60% susc.

Viridans: 30-60% susc.

NO enterococcus

NO GRAM - coverage
•High Na+ in IV forms, watch out in HTN patients
•Hepatically eliminated, do not need renal adjustment
Amino PCNs
Created to add some Gram - coverage
Agents
Ampicillin, Amoxicillin, Bacampicillin
Primary Coverage

GRAM +

Strep:

Pneumo, ABCG: >60% susc.

Viridans: 30-60% susc.

Staph Epi: >60%

Enterococcus (both): >60%
 GRAM  >60%: Proteus, Neisseria meningitidis
 30-60%: H. Influenzae, E. Coli,
Salmonella sp., Shigella sp.
- Anaerobes:
 >60%: Clostridium (not difficile),
Peptostreptococcus
 30-60%: Actinomyces
Anti-Pseudomonal PCNs
(Carboxypenicillins, Ureidopenicillins)
Agents
Piperacillin, Ticarcillin
Primary Coverage:

GRAM +

>60%: Strep Pneumo, Strep
ABCG

30-60%: Strep viridans,
Enterococcus (both)

Anaerobes:

>60%: Clostridium (not
difficile), Peptostreptococcus
 GRAM -
 >60%:
 Pseudomonas, Citrobacter,
Enterobacter, Proteus, E. Coli,
Salmonella, Shigella, Neisseria
 Klebsiella (Pip only), Serratia
(Ticar only)
 30-60%: H. Influenzae,
Moraxella (Pip only)
 Lactamase Inhibitor PCNs
Agents

Augmentin: PO

Amoxicillin/Clavulanate



Increase coverage to 
Lactamase Producing:
Timentin: IV
Ticarcillin/Clavulanate

Staph
Zosyn: IV

Neisseria
Piperacillin/Tazobactam

H. Influenzae

Klebsiella

Proteus
Unasyn: IV
Ampicillin/Sulbactam

Augmentin, Unasyn do NOT
cover Pseudomonas