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

1492 Serum sickness varies from mild fever, rash, and leukopenia to
severe arthralgia or arthritis, purpura, lymphadenopathy, splenomegaly,
mental changes, electrocardiographic abnormalities suggestive of
myocarditis, generalized edema, albuminuria, and hematuria. It is
mediated by IgG antibodies. This reaction is rare, but when it occurs,
it appears after penicillin treatment has been continued for 1 week or
more; it may be delayed, however, until 1 or 2 weeks after the drug has
been stopped. Serum sickness caused by penicillin may persist for a
week or longer.
Vasculitis of the skin or other organs may be related to penicillin
hypersensitivity. The Coombs reaction frequently becomes
positive during prolonged therapy with a penicillin or cephalosporin,
but hemolytic anemia is rare. Reversible neutropenia may occur. It
is not known if this is truly a hypersensitivity reaction; it has been
noted with all the penicillins and has been seen in up to 30% of
patients treated with 8-12 g nafcillin for >21 days. The bone marrow
shows an arrest of maturation.
Fever may be the only evidence of a hypersensitivity reaction
to the penicillins. It may reach high levels and be maintained,
remittent, or intermittent; chills occur occasionally. The febrile reaction
usually disappears within 24-36 hours after administration of
the drug is stopped but may persist for days.
Eosinophilia is an occasional accompaniment of other allergic
reactions to penicillin. At times, it may be the sole abnormality,
and eosinophils may reach levels of ≥10-20% of the total number of
circulating white blood cells.
Penicillins rarely cause interstitial nephritis; methicillin has
been implicated most frequently. Hematuria, albuminuria, pyuria,
renal cell and other casts in the urine, elevation of serum creatinine,
and even oliguria have been noted. Biopsy shows a mononuclear
infiltrate with eosinophilia and tubular damage. IgG is present in the
interstitium. This reaction usually is reversible.
Management of the Patient Potentially Allergic to Penicillin. Evaluation
of the patient’s history is the most practical way to avoid the use of
penicillin in patients who are at the greatest risk of adverse reaction.
Most patients who give a history of allergy to penicillin should be
treated with a different type of antibiotic. Unfortunately, there is no
totally reliable means to confirm a history of penicillin allergy (Romano
et al., 2003). Skin testing for IgE-mediated immediate-type responses
is compromised by the lack of a commercially available minor-determinant
mixture. A National Institute of Allergy and Infectious Diseases
(NIAID) multicenter study used major and minor determinants for skin
testing. Of 726 patients with a history of penicillin allergy, 566 had
negative skin tests. Of those, only 7 of 566 (1.2%) had possibly IgEmediated
immediate or accelerated penicillin allergy when given penicillin
(Sogn et al., 1992). Radioallergosorbent tests (RASTs) for IgE
antipenicilloyl determinants suffer from the same limitations as skin
tests (Weiss and Adkinson, 2005).
Occasionally, desensitization is recommended for penicillinallergic
patients who must receive the drug. This procedure consists
of administering gradually increasing doses of penicillin in the hope
of avoiding a severe reaction and should be performed only in an
intensive care setting. This may result in a subclinical anaphylactic
discharge and the binding of all IgE before full doses are administered.
Penicillin may be given in doses of 1, 5, 10, 100, and 1000
units intradermally in the lower arm, with 60-minute intervals
between doses. If this is well tolerated, then 10,000 and 50,000 units
may be given subcutaneously. Desensitization also may be accomplished
SECTION VII
CHEMOTHERAPY OF MICROBIAL DISEASES
by the oral administration of penicillin. When full doses are reached,
penicillin should not be discontinued and then restarted because
immediate reactions may recur (see Weiss and Adkinson, 2005, for
details). The patient should be observed constantly during the desensitizing
procedure, an intravenous line must be in place, and epinephrine
and equipment and expertise for artificial ventilation must
be on hand. It must be emphasized that this procedure may be dangerous,
and its efficacy is unproven.
Patients with life-threatening infections (e.g., endocarditis
or meningitis) may be continued on penicillin despite the development
of a maculopapular rash, although alternative antimicrobial
agents should be used whenever possible. The rash often resolves
as therapy is continued, perhaps owing to the development of
blocking antibodies of the IgG class. The rash may be treated with
antihistamines or glucocorticoids, although there is no evidence
that this therapy is efficacious. Rarely, exfoliative dermatitis with
or without vasculitis develops in these patients if therapy with
penicillin is continued.
Other Adverse Reactions. The penicillins have minimal direct toxicity.
Apparent toxic effects that have been reported include bone
marrow depression, granulocytopenia, and hepatitis. The last-named
effect is rare but is seen most commonly following the administration
of oxacillin and nafcillin. The administration of penicillin G,
carbenicillin, piperacillin, or ticarcillin has been associated with a
potentially significant defect of hemostasis that appears to be due to
an impairment of platelet aggregation; this may be caused by interference
with the binding of aggregating agents to platelet receptors
(Fass et al., 1987).
Most common among the irritative responses to penicillin
are pain and sterile inflammatory reactions at the sites of intramuscular
injections—reactions that are related to concentration. Serum
transaminases and lactic dehydrogenase may be elevated as a result
of local damage to muscle. In some individuals who receive penicillin
intravenously, phlebitis or thrombophlebitis develops. Many
persons who take various penicillin preparations by mouth experience
nausea, with or without vomiting, and some have mild to
severe diarrhea. These manifestations often are related to the dose
of the drug.
When penicillin is injected accidentally into the sciatic nerve,
severe pain occurs and dysfunction in the area of distribution of this
nerve develops and persists for weeks. Intrathecal injection of penicillin
G may produce arachnoiditis or severe and fatal encephalopathy.
Because of this, intrathecal or intraventricular administration of
penicillins should be avoided. The parenteral administration of large
doses of penicillin G (>20 million units per day, or less with renal
insufficiency) may produce lethargy, confusion, twitching, multifocal
myoclonus, or localized or generalized epileptiform seizures. These
are most apt to occur in the presence of renal insufficiency, localized
lesions of the central nervous system (CNS), or hyponatremia. When
the concentration of penicillin G in CSF exceeds 10 μg/mL, significant
dysfunction of the CNS is frequent. The rapid intravenous
administration of 20 million units of penicillin G potassium, which
contains 34 mEq of K + , may lead to severe or even fatal hyperkalemia
in persons with renal dysfunction.
Injection of penicillin G procaine may result in an immediate
reaction, characterized by dizziness, tinnitus, headache, hallucinations,
and sometimes seizures. This is due to the rapid liberation of