Side Effects

An important limitation is that antimicrobial drugs may

have side effects on the host. With antimicrobial chemotherapy,
the object is to optimize the therapeutic index,
the ratio between the effective and the toxic dose. It is
important to keep in mind that the degree of selectivity
chosen depends on the plight of the patient. Certain
inhibitors of folic acid metabolism, like methotrexate, are
very toxic in humans but are useful as anticancer or antiinf
ammatory agents.
Infectious agents that do not penetrate into deep tissues
are special cases in therapy. Topical applications for
skin infections are less likely to produce side effects. This
lack of side effects permits extensive use of agents that
can harm host cell membranes, such as the antibacterial
drug polymyxin and the antifungal antibiotic nystatin.
Drugs against intestinal worms, which are topologically
located outside body tissues (see Fig. 1-1), are also less
likely to cause side effects.
Occasionally, an astute clinical observation can turn
a side effect to an advantage. Some derivatives of sulfonamides
act as a diuretic and cause blood acidosis and alkaline
urine. Although these effects are weak, they led to the
synthesis of an important group of modern diuretics. Similarly,
some sulfa drugs produce hypoglycemia, which led to
the development of new drugs for the treatment of diabetes.
HOW ARE ANTIBIOTICS SELECTIVE?
In the case of sulfa drugs, selectivity is based on the fact
that, unlike humans, bacteria must synthesize their own
folic acid. Any step in metabolism, whether unique to
microorganisms or not, is a potential target for antimicrobial
action. All that is needed is selective toxicity. In the
same pathway as that affected by sulfonamides, the drug
trimethoprim blocks the function rather than the synthesis
of folic acid (see Fig. 5-2). Trimethoprim inhibits
the enzyme dihydrofolate reductase, which catalyzes
the reduction of dihydrofolate to tetrahydrofolate. This
enzyme is necessary for human cells as well as for bacteria,
but the amount needed to cause 50% enzyme inhibition is
0.005 mM for bacteria, 0.07 mM for protozoa, and 250 mM
for mammals. Thus, the drug can be used against bacteria
and protozoa at concentrations that do not harm humans.
This example of effi cacy is based on the relative
insensitivity of the host compared with bacterial targets.
In another example, both host cells and bacteria are
sensitive to tetracycline. However, unlike mammalian
cells, bacteria concentrate the antibiotic. As a result, tetracycline
is effective against even intracellular organisms
(e.g., chlamydiae).
The armamentarium of antimicrobials includes drugs
that affect the synthesis or function of every class of
microbial macromolecules. Extreme selectivity is achieved
when the biochemical target is absent in the host cells.
The best examples are the -lactam antibiotics (e.g., penicillin),
which affect the biosynthesis of the murein layer
of the bacterial cell wall (see Chapter 3). No comparable
structure exists in mammalian cells, which are therefore
totally insensitive to the action of these antibiotics. Nonetheless,
even -lactams can have undesirable side effects.
Some individuals cannot take them because they have
a strong allergic reaction. Also, administration of broadspectrum
-lactams can result in the destruction of the
normal intestinal microbiota. This effect can lead to colitis,
overgrowth by fungi, and other complications. Even a
nearly perfect antibiotic comes with a price.
HOW DO MICROBES CIRCUMVENT
THE ACTION OF ANTIBIOTICS?
The destructive power of antibiotics is so pervasive that
within a few years of their introduction, resistant organisms
can supplant susceptible ones. At what point in
the action of antibiotics does resistance come into play?
The action of antimicrobial drugs can be broken into a
sequence of three steps: First, the drugs must associate
with the bacteria and penetrate their envelope. Second,
they must be transported to an intracellular site of action.
Third, they must bind to their specifi c biochemical target.
Resistance to drugs can occur at each step. Microorganisms,
like sophisticated biochemists, have developed a
multitude of ways to become resistant. Resistance poses
a serious problem when it arises in a pathogenic microbe
capable of causing damage to human hosts. Following are
the clinically relevant mechanisms of resistance:
Synthesis of enzymes that break down the drug molecule
Chemical modifi cation of the drug that interferes with
its function
Prevention of access to the target site by inhibiting
uptake
Prevention of access to the target site by increasing
export of the drug from the microbial cell
Modifi cation of the target site
All these mechanisms have been recognized in clinical
pathogens, but the most common is the last one.
Some of the examples introduced in Chapter 3 are treated
more fully in the following paragraphs. A more extensive
list of mechanisms of antibacterial resistance is shown in
Table 5-1.
b-Lactams and Enzymes that
Inactivate Them
Chapter 3 summarized the effects of penicillins, cephalosporins,
and carbapenems on cell wall formation and their
consequences for bacterial survival. This group of drugs is
large, and for various