2 Antimicrobial Mechanisms of Action
Antimicrobial agents (i.e. drugs that exert bacteriostatic (limits bacterial growth) or
bactericidal (killing) effects) typically function through one of five mechanisms of
action. These comprise (Chambers 2006 ):
l Inhibition of cell wall synthesis. These agents are generally bactericidal.
l Alteration of the 30s and 50s ribosomal subunits, resulting in a reversible
inhibition of protein synthesis. These agents are generally bacteriostatic rather
than bactericidal.
l Inhibition of bacterial protein synthesis or the synthesis of aberrant proteins via
the binding of drug to the 30s ribosomal subunit. This ultimately results in cell
death (bactericidal).
l Alteration of nucleic acid metabolism. This usually leads to cell death
(bactericidal).
l Anti-metabolite activities. While this usually leads to bacteriostasis, it can result
in bactericidal effects under some circumstances.
Newer agents, such as daptomycin, interfere with cell membrane electrical
potential, leading to membrane depolarisation and cell death (Steenbergen et al.
2005 ).
It should be noted that the classical division of drugs into bacteriostatic and
bactericidal is somewhat artificial. There is a growing body of evidence that under
certain situations (e.g. 4–5 times the MIC) or for some pathogens, bacteriostatic
drugs may exert bactericidal activity. Conversely, at low concentrations relative to
the MIC (or even at one time the MIC) some bactericidal agents exert only
bacteriostatic effects.
While the magnitude of the inhibitory effect for some agents is primarily
dependent upon the duration of drug exposure, for others it is largely a function
of the rate and/or extent of drug exposure. This phenomenon was first recognised by
Shah et al. ( 1976 ) who, upon studying in vitro bacterial responses to constant
drug concentrations for variable periods of time, observed that the effects could
be classified as either time or concentration-dependent. In reality, most drug effects
are a function both of extent and duration of exposure. For example, fluoroquino-
lones, which are typically classified as concentration-dependent agents, can appear
to act in a time-dependent manner if drug concentrations at the site of action
decrease below bactericidal drug concentrations (i.e. the drug concentrations
needed to exert a killing effect) for a duration that exceeds the pathogen’s duration
of post-antibiotic effect (PAE). PAEs are discussed later in this section.
Drug classification of concentration-dependent or time-dependent killing is
primarily a function of the shape of its concentration-effect curve. The steeper the
curve, the smaller the impact of increasing drug concentrations on the antimicrobial
response. Conversely, the more shallow the curve, the greater the relationship
between the rate of bacterial kill versus the antimicrobial drug concentration.
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