Pharmacology for Anaesthesia and Intensive Care

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Section IVOther important drugs

R— C — N

C— OH

—

——

H

O

——

O

N

CH 3

CH 3

S

O

-lactam ring

Penicillins can be divided into:


Narrow spectrum penicillins (benzylpenicillin)


Narrow spectrum penicillins resistant to staphylococcal β-lactamase (flu-

cloxacillin)


Extended spectrum penicillins (ampicillin)


Anti-pseudomonal penicillins (piperacillin)

Mechanism of action

Penicillins are bactericidal antibiotics that inhibit cell wall synthesis. The intactβ-

lactam ring binds to various proteins, the most important of which are transpeptidase

and carboxypeptidase. Once these proteins are bound, peptidoglycan cross-linkage

is prevented and the cell wall becomes weakened. The consequences of this vary

according to the bacterial species being attacked.

Gram-positive cocci possess a thick peptidoglycan cell wall. When exposed toβ-

lactams, growth continues at a normal rate (with reduced cross-linkage) until the

cell wall becomes weakened and lysis is inevitable. This is further assisted by the

early release of a bacterial cellular component – lipoteichoic acid (a bacterial sugar

alcohol phosphate). This component is intrinsically able to accelerate peptidoglycan

breakdown and cell death. In spite of this, the use ofβ-lactams against susceptible

gram-positive cocci rarely results in bacterial killing to the point of extinction. A

significant number ofβ-lactam sensitive cells, known aspersistors,will remain dor-

mant until the antibiotic is removed. Extinction can be achieved, however, by the

addition of a synergistic antibiotic such as an aminoglycoside, whose potency is fur-

ther enhanced by the penicillin-induced peptidoglycan damage allowing gentamicin

better intracellular penetration.

Gram-negative bacilli possess a thinner peptidoglycan wall surrounded by a

lipopolysaccharide-lipoprotein envelope. Minimal damage to this layer weakens

the cell wall and as a result of internal hydrostatic pressures, the bacteria become

spherical (i.e. forms spheroplasts). Spheroplasts will lyse if placed in a hypo-osmolar

environment, however, bacilli likeHaemophilus influenzae(H. influenzae)have such

alowintracellular osmolality that they rarely become osmotically challenged to

the point where cell death occurs. When the antibiotic is removed, peptidoglycan

integrity is restored; they reform bacilli and continue to divide normally.

Penicillin is also rendered ineffective byβ-lactamase, which hydrolyzes theβ-

lactam ring. Various varieties of this enzyme exist with gram-positiveβ-lactamase