3rd Lecture
By
Abdelkader Ashour, Ph.D. Phone: 4677212 Email: [email protected]
DENS 521Clinical Dental Therapeutics
Resistance to -lactams
I. Production of -lactamases Bacteria can destroy -lactam antibiotics enzymatically by a group of
enzymes called - lactamases The production of -lactamases is considered the principal cause of bacterial
resistance to -lactam antibiotics The introduction of new classes of -lactams has invariably been followed by
the emergence of new -lactamases capable of degrading them, as an example of rapid bacterial evolution under a rapidly changing environment
Some -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 -lactam antibiotics
Resistance to -lactams I. Production of -lactamases, contd. -Lactamases are grouped into four classes:
Class A -lactamases include the extended-spectrum -lactamases, which degrade penicillins, some cephalosporins and carbapenems
I. Class B -lactamases are Zn2+-dependent enzymes that destroy almost all -lactams
II. Class C -lactamases are active against cephalosporins
III. Class D includes cloxacillin-degrading enzymes. They also are active against some cephalosporins
Class A and D enzymes are inhibited by the commercially available -lactamase inhibitors, such as clavulanate and sulbactam
Examples of bacteria that produce -lactamases are staphylococcus aureus and many strains of H. influenzae, Neisseria and Pseudomonas
Resistance to -lactamsII. 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 -lactam antibiotics
Example 2: Cephalosporin resistance in Streptococcus pneumoniae is caused by altered PBPs (2 of the 5 high molecular weight PBPs)
Resistance to -lactamsIII. 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 -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 -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 -lactam resistance in P. aeruginosa, E. coli and Neisseria gonorrhoeae
Examples of Penicillins
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 anaerobesNot active against: most gram-negative aerobic organismsPenicillin G is the dug of choice for infections due to Neisseria meningitidis,
Bacillus anthracis, Clostridium perfringens and tetani, Corynebacterium diphtheriae and Treponema pallidum…..
Classification of Penicillins, On the Basis of Antibacterial Spectrum
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 uncommonThe most important adverse effects are due to hypersensitivity with manifestations
ranging from skin eruptions to anaphylactic shock
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 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)
Classification of Penicillins, On the Basis of Antibacterial Spectrum
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 -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 -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
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
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 -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 -lactamase inhibitor might be of value These infections include infected animal and human bites, odontogenic infections,
chronic sinusitis and intra-abdominal infections
-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®)
Classification of Penicillins, On the Basis of Antibacterial Spectrum