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DENS 521
Clinical Dental Therapeutics
3rd Lecture
By
Abdelkader Ashour, Ph.D.
Phone: 4677212
Email: [email protected]
Resistance to b-lactams
I. Production of b-lactamases
 Bacteria can destroy b-lactam antibiotics enzymatically by a group of
enzymes called b- lactamases
 The production of b-lactamases is considered the principal cause of bacterial
resistance to b-lactam antibiotics
 The introduction of new classes of b-lactams has invariably been followed by
the emergence of new b-lactamases capable of degrading them, as an
example of rapid bacterial evolution under a rapidly changing environment
 Some b-lactamases are relatively substrate specific, and these are described
as either penicillinases or cephalosporinases
 Other "extended spectrum" enzymes are less discriminant and can hydrolyze
a variety of b-lactam antibiotics
Resistance to b-lactams
I. Production of b-lactamases, contd.
 b-Lactamases are grouped into four classes:
Class A b-lactamases include the extended-spectrum b-lactamases,
which degrade penicillins, some cephalosporins and carbapenems
Class B b-lactamases are Zn2+-dependent enzymes that destroy almost
all b-lactams
Class C b-lactamases are active against cephalosporins
Class D includes cloxacillin-degrading enzymes. They also are active
against some cephalosporins
 Class A and D enzymes are inhibited by the commercially available blactamase inhibitors, such as clavulanate and sulbactam
 Examples of bacteria that produce b-lactamases are staphylococcus
aureus and many strains of H. influenzae, Neisseria and Pseudomonas
Resistance to b-lactams
II. The occurrence of PBPs with low affinity to cephalosporins
 The microorganism may be intrinsically resistant because of structural
differences in the PBPs that are the targets of these drugs
 A sensitive strain may acquire resistance of this type by the development of
high-molecular-weight PBPs that have decreased affinity for cephalosporins
and penicillins, requiring clinically unattainable concentrations of the drug to
effect its bactericidal activity
 Example 1: Methicillin-resistant S. aureus (MRSA) are resistant by means of
acquisition of an additional high-molecular-weight PBP with a very low affinity
for all b-lactam antibiotics
 Example 2: Cephalosporin resistance in Streptococcus pneumoniae is caused
by altered PBPs (2 of the 5 high molecular weight PBPs)
Resistance to b-lactams
III. Decreased permeability to the drug
 Decreased penetration through the outer membrane prevents the drug from
reaching the target PBP
 In G+ve bacteria, the peptidoglycan polymer is very near the cell surface, thus
the small b-lactam antibiotic molecules can penetrate easily to the PBPs,
where the final stages of the synthesis of the peptidoglycan take place
 G-ve organisms have an outer membrane that limits penetration of b-lactam
antibiotics
 Some small hydrophilic antibiotics can diffuse through aqueous channels in
the outer membrane that are formed by proteins called porins
 An extreme example is P. aeruginosa, which is intrinsically resistant to a wide
variety of antibiotics because it lacks the classical high-permeability porins
 Active efflux pump serves as another mechanism of resistance, removing the
antibiotic from its site of action before it can act
 This is an important mechanism of b-lactam resistance in P. aeruginosa, E. coli
and Neisseria gonorrhoeae
Examples of Penicillins
Classification of Penicillins,
On the Basis of Antibacterial Spectrum
I. Narrow-spectrum:
1. Natural Penicillins
 Examples: benzylpenicillin (penicillin G), phenoxymethylpenicillin (penicillin V)
 Active against:
most gram-positive bacteria with the exception of penicillinase-producing S. aureus
most Neisseria species and some gram-negative anaerobes
 Not active against: most gram-negative aerobic organisms
 Penicillin G is the dug of choice for infections due to Neisseria meningitidis,
Bacillus anthracis, Clostridium perfringens and tetani, Corynebacterium diphtheriae
and Treponema pallidum…..
 Penicillin V is less active than penicillin G against Neisseria species. It is
satisfactory substitute for penicillin G against Streptococcus pneumonia and S.
pyogenes. It is the first choice in the treatment of odontogenic infections
 Tetracycline, a bacteriostatic antibiotic, may antagonize the bactericidal effect of
penicillin, and concurrent use of these drugs should be avoided
 Adverse effects are generally uncommon
 The most important adverse effects are due to hypersensitivity with manifestations
ranging from skin eruptions to anaphylactic shock
Classification of Penicillins,
On the Basis of Antibacterial Spectrum
I. Narrow-spectrum Penicillins:
1. Natural Penicillins, contd.
 Pharmacokinetics:
 Penicillin G diffuses widely, attaining therapeutic concentrations in most body
tissues
 The t1/2 of penicillin G is less than 1 hour and it is eliminated primarily by renal
tubular secretion. This secretion can be inhibited by probenecid (this would
prolong serum penicillin levels)
 Because renal dysfunction will compromise the elimination of penicillin, dosages
may need to be reduced in patients with renal insufficiency (esp. in severe cases)
 Procaine penicillin is best suited to the single-dose outpatient treatment of very
sensitive organisms (e.g., penicillin-sensitive N. gonorrhea and group A
streptococci)
 Benzathine penicillin is another long-acting preparation given IM. It is used for
prophylaxis of rheumatic fever and for treatment of syphilis
 Penicillin V is a much more resistant to gastric acid than is penicillin G and
therefore better absorbed from the GIT. It is the orally-active form of penicillin
 All oral penicillins are best given on an empty stomach to avoid the absorption
delay caused by food
Classification of Penicillins,
On the Basis of Antibacterial Spectrum
I. Narrow-spectrum, contd.
2. Beta-Lactamase Resistant Penicillins
 Examples: methicillin, dicloxacillin, flucloxacillin
 Antibacterial Activity:
These penicillins are resistant to staphylococcal lactamases
They are also active against other bacteria for which penicillin G is indicated, but
they are much less active than penicillin G
II. Broad Spectrum Penicillins
 Examples: aminopenicillins such as ampicillin and amoxicillin
 These drugs retain the antibacterial spectrum of penicillin and have improved
activity against G-ve organisms
 They are destroyed by b-lactamases
 Ampicillin and amoxicillin are among the most useful antibiotics for treating
children suffering from infections caused by sensitive G-ve aerobic bacteria,
enterococci, and b-lactamase-negative H. influenzae
 Amoxicillin is the favored drug for the treatment of acute otitis media
 Plasma concentrations of amoxicillin are usually twice those of ampicillin after an
equivalent oral dose. The distribution and excretion characteristics of these
penicillins are similar to those of penicillin
Classification of Penicillins,
On the Basis of Antibacterial Spectrum
3. Anti-Pseudomonal Penicillins
 Examples: pipracillin, azlocillin and mezlocillin
 These antibiotics have a broader spectrum of G-ve activity than do the
aminopenicillins, and include activity against most strains of P. aeruginosa
 These antibiotics are used in the treatment of urinary tract, lung and
bloodstream infections caused by ampicillin-resistant enteric G-ve pathogens
 Beta-lactamase Inhibitors
 These drugs competitively inhibit b-lactamase enzymes, restoring the original
spectrum of activity to enzyme-susceptible antibiotics
 Some infections are polymicrobial and may involve anaerobes; for these the
addition of a b-lactamase inhibitor might be of value
 These infections include infected animal and human bites, odontogenic infections,
chronic sinusitis and intra-abdominal infections
 b-lactamase inhibitors in clinical use include clavulanic acid (usually combined
with amoxicillin  Augmentin®), sulbactam (usually combined with ampicillin 
Unasyn®) and tazobactam (usually combined with piperacillin  Zosyn®)