3rd Lecture

By

Abdelkader Ashour, Ph.D. Phone: 4677212 Email: aeashour@ksu.edu.sa

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