DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

Untoward Reactions to Penicillins
Hypersensitivity Reactions. Hypersensitivity reactions
are by far the most common adverse effects noted with
the penicillins, and these agents probably are the most
common cause of drug allergy. Allergic reactions complicate
0.7-4% of all treatment courses. There is no convincing
evidence that any single penicillin differs from
the group in its potential for causing true allergic reactions.
In approximate order of decreasing frequency,
manifestations of allergy to penicillins include maculopapular
rash, urticarial rash, fever, bronchospasm,
vasculitis, serum sickness, exfoliative dermatitis, Stevens-
Johnson syndrome, and anaphylaxis (Weiss and Adkinson,
2005). The reported overall incidence of such reactions
to the penicillins is 0.7-10%. Hypersensitivity to penicillins
generally extends to the other β-lactams (e.g.,
cephalosporins, some carbapenems).
Hypersensitivity reactions may occur with any dosage form
of penicillin; allergy to one penicillin exposes the patient to a greater
risk of reaction if another is given. But the occurrence of an untoward
effect does not necessarily imply repetition on subsequent exposures.
Hypersensitivity reactions may appear in the absence of a previous
known exposure to the drug. This may be caused by unrecognized
prior exposure to penicillin in the environment (e.g., in foods of animal
origin or from the fungus-producing penicillin). Although elimination
of the antibiotic usually results in rapid clearing of the allergic
manifestations, they may persist for 1-2 weeks or longer after therapy
has been stopped. In some cases, the reaction is mild and disappears
even when the penicillin is continued; in others, immediate
cessation of penicillin treatment is required. In a few instances, it is
necessary to interdict the future use of penicillin because of the risk
of death, and the patient should be so warned. It must be stressed that
fatal episodes of anaphylaxis have followed the ingestion of very
small doses of this antibiotic or skin testing with minute quantities of
the drug.
Penicillins and their breakdown products act as haptens after
covalent reaction with proteins. The most abundant breakdown product
is the penicilloyl moiety (major determinant moiety [MDM]),
which is formed when the β-lactam ring is opened. A large percentage
of immunoglobulin (Ig)E-mediated reactions are to the MDM, but at
least 25% of reactions are to other breakdown products, and the severities
of the reactions to the various components are comparable. These
products are formed in vivo and can be found in solutions of penicillin
prepared for administration. The terms major and minor determinants
refer to the frequency with which antibodies to these haptens appear
to be formed. They do not describe the severity of the reaction that
may result. In fact, anaphylactic reactions to penicillin usually are
mediated by IgE antibodies against the minor determinants.
Antipenicillin antibodies are detectable in virtually all
patients who have received the drug and in many who have never
knowingly been exposed to it. Recent treatment with the antibiotic
induces an increase in major-determinant-specific antibodies that
are skin sensitizing. The incidence of positive skin reactors is three
to four times higher in atopic than in nonatopic individuals. Clinical
and immunological studies suggest that immediate allergic reactions
are mediated by skin-sensitizing or IgE antibodies, usually of
minor-determinant specificities. Accelerated and late urticarial reactions
usually are mediated by major-determinant–specific skin-sensitizing
antibodies. The recurrent-arthralgia syndrome appears to
be related to the presence of skin-sensitizing antibodies of minordeterminant
specificities. Some maculopapular and erythematous
reactions may be due to toxic antigen-antibody complexes of majordeterminant-specific
IgM antibodies. Accelerated and late urticarial
reactions to penicillin may terminate spontaneously because of
the development of blocking antibodies.
Skin rashes of all types may be caused by allergy to penicillin.
Scarlatiniform, morbilliform, urticarial, vesicular, and bullous
eruptions may develop. Purpuric lesions are uncommon and usually
are the result of a vasculitis; thrombocytopenic purpura may occur
very rarely. Henoch-Schönlein purpura with renal involvement has
been a rare complication. Contact dermatitis is observed occasionally
in pharmacists, nurses, and physicians who prepare penicillin
solutions. Fixed-drug reactions also have occurred. More severe
reactions involving the skin are exfoliative dermatitis and exudative
erythema multiforme of either the erythematopapular or vesiculobullous
type; these lesions may be very severe and atypical in distribution
and constitute the characteristic Stevens-Johnson syndrome.
The incidence of skin rashes appears to be highest following the use
of ampicillin, at ~9%; rashes follow the administration of ampicillin
in nearly all patients with infectious mononucleosis. When allopurinol
and ampicillin are administered concurrently, the incidence of
rash also increases. Ampicillin-induced skin eruptions in such
patients may represent a “toxic” rather than a truly allergic reaction.
Positive skin reactions to the major and minor determinants of penicillin
sensitization may be absent. The rash may clear even while
administration of the drug is continued.
The most serious hypersensitivity reactions produced by the
penicillins are angioedema and anaphylaxis. Angioedema, with
marked swelling of the lips, tongue, face, and periorbital tissues, frequently
accompanied by asthmatic breathing and “giant hives,” has
been observed after topical, oral, or systemic administration of penicillins
of various types.
Acute anaphylactic or anaphylactoid reactions induced by
various preparations of penicillin constitute the most important
immediate danger connected with their use. Among all drugs, the
penicillins are most often responsible for this type of untoward
effect. Anaphylactoid reactions may occur at any age. Their incidence
is thought to be 0.004-0.04% in persons treated with penicillins
(Kucers and Bennett, 1987). About 0.001% of patients treated
with these agents die from anaphylaxis. It has been estimated that at
least 300 deaths per year are due to this complication of therapy.
About 70% have had penicillin previously, and one-third of these
reacted to it on a prior occasion. Anaphylaxis most often has followed
the injection of penicillin, although it also has been observed
after oral ingestion of the drug and even has resulted from the intradermal
instillation of a very small quantity for the purpose of testing
for the presence of hypersensitivity. The clinical pictures that develop
vary in severity. The most dramatic is sudden, severe hypotension
and rapid death. In other instances, bronchoconstriction with severe
asthma; abdominal pain, nausea, and vomiting; extreme weakness
and a fall in blood pressure; or diarrhea and purpuric skin eruptions
have characterized the anaphylactic episodes.
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CHAPTER 53
PENICILLINS, CEPHALOSPORINS, AND OTHER β-LACTAM ANTIBIOTICS