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DENS 521
Clinical Dental Therapeutics
5th Lecture
By
Abdelkader Ashour, Ph.D.
Phone: 4677212
Email: [email protected]
Other Beta Lactam Drugs,
Overview
 These are important therapeutic agents with a b-lactam structure that are
neither penicillins nor cephalosporins
 This group of inhibitors of cell wall synthesis includes:
 Monobactams
 Carbapenems
 Beta-Lactamase Inhibitors (such as clavulanic acid, sulbactam and
tazobactam)
 These agents were developed to deal with β-lactamase-producing
organisms
Monobactams
 Monobactams are drugs with a monocyclic blactam ring
 They are relatively resistant to b-lactamases and
active against G-ve bacteria (including
pseudomonas)
 They have no activity against G+ve bacteria or anaerobes
 The main monobactam is aztreonam, which is resistant to many of the β-lactamases
that are produced by most G-ve bacteria
 Aztreonam is isolated from Chromobacterium violaceum
 Aztreonam is effective only against G-ve aerobic organisms such as
pseudomonads, Neisseria meningitidis and Haemophilus influenzae. Its activity
against Enterobacteriaceae is excellent
 It is given parenterally and has a plasma half-life of 2 hours, and most of the drug is
recovered unaltered in the urine
 It generally is well tolerated. Patients who are allergic to penicillins or cephalosporins
appear not to react to aztreonam, with the exception of ceftazidime
Carbapenems
 Carbapenems are β-lactams that contain a fused βlactam ring and a five-membered ring system that differs
from the penicillins in being unsaturated and containing a
carbon atom instead of the sulfur atom
 This class of antibiotics has a broader spectrum of activity
than do most other β-lactam antibiotics
 Imipenem, a carbapenem, is very resistant to hydrolysis by most β-lactamases
 It has a very broad spectrum of antimicrobial activity, being active against many aerobic
and anaerobic G+ve and G-ve (including P. aeruginosa) organisms
 It is sometimes given together with cilastatin, which inhibits its inactivation by renal
enzymes
 Meropenem is similar to imipenem but is not metabolized by the kidney
 Imipenem is not absorbed orally. Both imipenem and cilastatin have a t1/2 of about 1h.
When administered concurrently with cilastatin, about 70% of it is recovered in the urine
as the active drug. Dosage should be modified for patients with renal insufficiency
 Nausea and vomiting are the most common adverse reactions. Neurotoxicity can occur
with high doses
 Patients who are allergic to other b-lactam antibiotics may have hypersensitivity reactions
when given imipenem
Beta-Lactamase Inhibitors
 These drugs can inactivate b-lactamases, thus prevent
the destruction of b-lactam antibiotics that are
substrates for these enzymes
 An important example is clavulanic acid
 It is produced by Streptomyces clavuligerus
Clavulanic acid
 It has poor intrinsic antimicrobial activity, but it is a "suicide" inhibitor that irreversibly
binds b-lactamases produced by many G+ve and G-ve microorganisms
 It is well absorbed by mouth and also can be given parenterally
 It is combined with amoxicillin as an oral preparation (Augmentin®) and with ticarcillin as
a parenteral preparation (Timentin®)
 Amoxicillin plus clavulanate is effective against b-lactamase-producing strains of
staphylococci, H. influenzae, gonococci and E. coli
 It is also used for treatment of acute otitis media in children, sinusitis & animal bite wounds
 The addition of clavulanate to ticarcillin extends its spectrum such that it resembles
imipenem to include aerobic G-ve bacilli, S. aureus and Bacteroides spp.
 Sulbactam is similar in structure to clavulanic acid. It is given orally or parenterally along
with a b-lactam antibiotic. It is available for IV or IM use combined with ampicillin
(Unasyn®), which has good activity against G+ve cocci, including b-lactamase-producing
strains of S. aureus, G-ve aerobes (but not Pseudomonas) and anaerobes

It is also effective for the treatment of mixed intra-abdominal and pelvic infections
Other Cell Wall or Membrane-active Agents
Vancomycin
 Vancomycin is an antibiotic produced by Streptococcus orientalis
 Vancomycin is primarily active against G+ve bacteria (e.g., S. pyogenes, S.
pneumoniae)
 MOA:

It inhibits cell wall synthesis by binding firmly to the D-Ala-D-Ala terminus of
the cell wall precursor unit attached to its lipid carrier

This inhibits the transglycosylase, preventing further elongation of
peptidoglycan and cross-linking

The peptidoglycan is thus weakened, and the cell becomes susceptible to lysis

The cell membrane is also damaged, which contributes to the antibacterial
effect

It is thus bactericidal for dividing microorganisms
 Resistance: Vancomycin resistance is due to expression of enzymes that modify
cell wall precursor by substituting a terminal D-lactate for D-alanine, reducing
vancomycin binding affinity by 1000 times
Other Cell Wall or Membrane-active Agents,
Vancomycin, Its structure
The transpeptidation
reaction in that is
inhibited by b-lactam
antibiotics
Θ
b-Lactam
antibiotics
Mechanism of Action, In motion
Inhibition of bacterial cell wall synthesis,
MOA of Vancomycin
Other Cell Wall or Membrane-active Agents,
Vancomycin
 Vancomycin is poorly absorbed from the GIT
 It can be administered orally to patients with pseudomembranous colitis,
although metronidazole is preferred
 Parenteral doses must be administered intravenously
 Ninety percent of the drug is excreted by glomerular filtration. In the
presence of renal insufficiency, unusual accumulation may occur
 It should be used only to treat serious infections:
 Management of infections due to methicillin-resistant staphylococci, including
pneumonia & endocarditis
 Management of severe staphylococcal infections in patients who are allergic to
penicillins and cephalosporins
 Management of known or suspected penicillin-resistant pneumococcal infections
Other Cell Wall or Membrane-active Agents,
Vancomycin
 Side Effects:
 Hypersensitivity reactions e.g., macular skin rashes and anaphylaxis
 Rapid I.V. infusion may cause erythematous or urticarial reactions, flushing,
tachycardia and hypotension
The extreme flushing that can occur is sometimes called "red-neck" or "redman" syndrome
This is not an allergic reaction but a direct toxic effect of vancomycin on mast
cells, causing them to release histamine
 Auditory impairment, sometimes permanent, may follow the use of this drug.
Ototoxicity is associated with excessively high concentrations of the drug in
plasma
The "peak" concentration should remain below 60 mg/ml to avoid ototoxicity
 Nephrotoxicity has become an unusual side effect when appropriate doses are
used, as judged by renal function and determinations of blood levels of the drug
Caution must be exercised when ototoxic or nephrotoxic drugs, such as
aminoglycosides, are administered concurrently or in patients with impaired
renal function