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Antimicrobials in the forms of antibacterials, antifungals, and antivirals have added significantly to the clinical care of infected patients since the introduction of penicillin in the 1940s. The development of drug-resistant strains of these pathogens has greatly expanded the number of antimicrobials necessary, and this has increased the overall potential for toxicity after use. Fortunately, toxicity due to acute overdose and even chronic therapeutic doses does not preclude their appropriate use in the majority of patients. HISTORY AND EPIDEMIOLOGY The majority of the adverse effects related to antimicrobials occur as a result of iatrogenic complications rather than intentional overdose. The diverse origins of these complications include dosing, route and decision errors, allergic reactions, adverse drug effects, and drug-drug interactions. Prevention in the form of process improvements and information regarding populations at risk for adverse drug effects is required to minimize these untoward events. Dosing errors are com-mon in neonates and infants, necessitating careful and constant dili-gence on the part of all healthcare providers. Antimicrobials are more commonly associated with anaphylactic reactions than are other xenobiotics. The reason for this is unclear, but it may be a result of their high frequency of use, repeated interrupted expo-sures caused by intermittent prescriptive use, or environmental contami-nation. A complete and clear allergy history is essential to minimize these adverse events in patients being considered for antimicrobial therapy. Many adverse effects attributed to antimicrobials are difficult to predict even when given patient-and population-specific parameters. In some cases, a diluent or an excipient is responsible for the adverse effect, as recognized with the use of procaine penicillin G in patients with procaine allergy. Antimicrobials are involved in many of the common and severe drug interactions, primarily through the inhibi-tion of metabolic enzymes. Patients being considered for antimicrobial therapy should be carefully assessed for the use of concomitant drug therapy that may be pharmacokinetically or pharmacodynamically affected by the chosen antimicrobial.
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817
CHAPTER 56
ANTIBACTERIALS,
ANTIFUNGALS, AND
ANTIVIRALS
Christine M. Stork
Antimicrobials in the forms of antibacterials, antifungals, and antivirals
have added significantly to the clinical care of infected patients since
the introduction of penicillin in the 1940s. The development of drug-
resistant strains of these pathogens has greatly expanded the number
of antimicrobials necessary, and this has increased the overall potential
for toxicity after use. Fortunately, toxicity due to acute overdose and
even chronic therapeutic doses does not preclude their appropriate use
in the majority of patients.
HISTORY AND EPIDEMIOLOGY
The majority of the adverse effects related to antimicrobials occur as
a result of iatrogenic complications rather than intentional overdose.
The diverse origins of these complications include dosing, route and
decision errors, allergic reactions, adverse drug effects, and drug-drug
interactions. Prevention in the form of process improvements and
information regarding populations at risk for adverse drug effects is
required to minimize these untoward events. Dosing errors are com-
mon in neonates and infants, necessitating careful and constant dili-
gence on the part of all healthcare providers.
Antimicrobials are more commonly associated with anaphylactic
reactions than are other xenobiotics. The reason for this is unclear, but it
may be a result of their high frequency of use, repeated interrupted expo-
sures caused by intermittent prescriptive use, or environmental contami-
nation. A complete and clear allergy history is essential to minimize these
adverse events in patients being considered for antimicrobial therapy.
Many adverse effects attributed to antimicrobials are difficult to
predict even when given patient- and population-specific parameters.
In some cases, a diluent or an excipient is responsible for the adverse
effect, as recognized with the use of procaine penicillin G in patients
with procaine allergy. Antimicrobials are involved in many of the
common and severe drug interactions, primarily through the inhibi-
tion of metabolic enzymes. Patients being considered for antimicrobial
therapy should be carefully assessed for the use of concomitant drug
therapy that may be pharmacokinetically or pharmacodynamically
affected by the chosen antimicrobial.
PHARMACOLOGY AND TOXICOLOGY
Antimicrobial pharmacology is aimed at the destruction of micro-
organisms through the inhibition of cell-cycle reproduction or the
altering of a critical function within a microorganism.
Table 56–1 lists
antimicrobials and their associated mechanisms of activity. Often the
mechanisms for toxicologic effects following acute overdose differ
from the therapeutic mechanisms.
Table 56–1 also lists the toxicologic
effects and related mechanisms.
Table 56–2 lists the pharmacokinetics
of each class of drugs.
ANTIBACTERIALS
AMINOGLYCOSIDES
O
C
R
1
H
NR
2
H
2
NH
2
N
O
HO
NH
2
O
HO
NH
OH
H
3
C
CH
3
Gentamicin C1: R1 = R2 = CH3
Gentamicin C2: R1 = CH3, R2 = H
Gentamicin C1a: R1 = R2 = H
Aminoglycoside antimicrobials that are in current use in the United
States include amikacin, gentamicin, kanamycin, neomycin, netilmi-
cin, streptomycin, and tobramycin.
Since aminoglycosides are only available in parenteral, topical, and
ophthalmic forms, overdoses are almost exclusively the result of dos-
ing errors. Fortunately, overdoses are rarely life threatening, and most
patients can be safely managed with minimal intervention.
28, 136 The
adverse effects of aminoglycosides are generally class based, although
subtle differences may exist in the potency with which the adverse
effects occur (
Table 56–3 ).
Large intravenous doses of aminoglycosides are both sufficiently
effective and safe for use in single daily doses.
4 Rarely, acute amino-
glycoside overdose results in nephrotoxicity, ototoxicity, or vestibular
toxicity. 131, 157 In one reported case, postmortem analysis confirmed
complete loss of hair cells in the inner and outer cochlear (Chap. 20).
D.
ANTIMICROBIALS
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818 Part C The Clinical Basis of Medical Toxicology
Aminoglycosides may exacerbate neuromuscular blockade, par-
ticularly at times corresponding to high-peak serum aminoglycoside
concentrations (Chap. 68).
187 Aminoglycosides inhibit the release of
acetylcholine from presynaptic nerve terminals by antagonism of the
aminoglycoside of the presynaptic calcium channel. Risk factors for
enhanced neuromuscular blockade include patients with abnormal
neuromuscular junction function, such as those with myasthenia gravis
and botulism.
Adverse Effects Associated With Therapeutic Use Adverse effects, includ-
ing nephrotoxicity and ototoxicity, correlate more closely with elevated
trough serum concentrations than with elevated peak concentrations. 120, 166
Less common adverse effects associated with chronic use include electro-
lyte abnormalities, allergic reactions, hepatotoxicity, anemia, granulocy-
topenia, thrombocytopenia, eosinophilia, retinal toxicity, reproductive
dysfunction, tetany, and psychosis.
62, 125, 142, 229, 244 When aminoglycosides
are administered at high doses or during once-daily dosing, sepsis-like
reactions, including chills and malaise, can occur.
51 This is likely a result
of excipients that are delivered to the patient during the infusion.
Nephrotoxicity The mechanism of nephrotoxicity and ototoxicity is
incompletely understood, but appears to include the formation of
reactive oxygen species in the presence of iron. Mitochondrial res-
piration is inhibited, lipid peroxidation occurs, and stimulation of
TABLE 56–1. Antimicrobial Pharmacology and Adverse Effects
Antimicrobial Mechanism
Antimicrobial of Action Acute Overdose Chronic Administration
Antibacterials
Aminoglycosides Inhibits 30s ribosomal subunit Neuromuscular blockade —inhibits Nephrotoxicity/ototoxicity—forms an iron
the release of acetylcholine from complex that inhibits mitochondrial
presynaptic nerve terminals and acts as respiration and causes lipid peroxidation
an antagonist at acetylcholine receptors
Penicillins, Inhibits cell wall mucopeptide Seizures—agonist at picrotoxin binding Hypersensitivity—immune
cephalosporins, synthesis site causing GABA antagonism Other—see text
and other β-lactams
Chloramphenicol Inhibits 50s ribosomal subunit Cardiovascular collapse “Gray baby syndrome”
and inhibits protein synthesis in Same as mechanism of action
rapidly dividing cells
Fluoroquinolones Inhibits DNA topoisomerase and Same as mechanism of action; binds to Not entirely known; binds to cations (Mg2+),
DNA gyrase cations (Mg
2+ ), seizures tendon rupture, hyper- and hypoglycemia
Linezolid Inhibits bacterial protein synthesis None clinically relevant MAOI activity: vasopressor response to
through inhibition of tyramine; serotonin syndrome with SSRI
N -formylmethionyl-t RNA and possibly meperidine
Macrolides, Inhibit 50s ribosomal subunit in Prolong QT; block delayed rectifier Not entirely known; cytotoxic effect;
lincosamides, multiplying cells potassium channel exacerbation of myasthenia gravis
and ketolides
Nitrofurantoin Bacterial enzymatic inhibitor Gastritis Dermatologic, hematologic, pancreatitis,
partotitis, hepatitis, crystaluria, pulmonary
fibrosis
Sulfonamides Inhibit para -aminobenzoic acid None clinically relevant Hypersensitivity—metabolite acts as hapten
and/or para -amino glutamic acid leading to hemolysis/methemoglobinemia—
in the synthesis of folic acid exposure to UVB causes free radical
formation
Tetracycline Inhibits 30s and 50s ribosomal None clinically relevant Unknown
subunits; binds to aminoacyl
transfer RNA
Vancomycin Inhibits glycopeptidase polymerase in “Red-man syndrome”—anaphylactoid Unknown
cell wall synthesis
Antifungal
Amphotericin B Binds with ergosterol on cytoplasmic Same as mechanism of action Nephrotoxicity—vehicle deoxycholate may
membrane to cause pores to facilitate be involved; nephrocalcinosis
organelle leak
Triazoles and Increases permeability of cell None clinically relevant None clinically relevant
imidazoles membranes ?CYP inhibition
γ-aminobutyric acid; MAOI, monoamine oxidase inhibitor; SSRI, selective serotonin reuptake inhibitor; UVB, ultraviolet B.
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Chapter 56 Antimicrobials, Antifungals, and Antivirals
previous aminoglycoside therapy, liver dysfunction, large total dose,
long duration of therapy, frequent doses, high trough concentrations,
presence of other nephrotoxic drugs, and shock.
9, 170 Because the uptake
of aminoglycosides into organs is saturable, appropriate once-daily
high-dose regimens are less problematic than several lesser doses given
in a single day.
Ototoxicity Ototoxicity can occur after acute or prolonged exposure to
aminoglycosides. 105 Both cochlear and vestibular dysfunction are corre-
lated with high trough aminoglycoside concentrations. Because amino-
glycosides bioaccumulate in the endolymph and perilymph spaces,
they have prolonged contact time with sensory hair cells. Vestibular
toxicity, caused by destruction of sensory receptor portions of the inner
ear or destruction of hair cells in the utricle and saccule, occurs in 0.4%
to 10% of patients. Symptoms include vertigo or tinnitus.
Table 56–3
details the relative characteristic toxicity of various aminoglycosides.
Full-tone audiometric testing may first show high-frequency hearing
loss, which may subsequently progress. Given the inability of cochlear
hair cells to regenerate, all hearing loss that develops is permanent.
Electronystagmography is the diagnostic tool of choice for vestibular
dysfunction, and up to 63% of patients with early findings of ves-
tibular dysfunction may improve after discontinuation of the drug.
124
Simultaneous administration of other ototoxic xenobiotics enhances
the ototoxicity of aminoglycosides (Chap. 20).
Withdrawal of the offending xenobiotic is indicated in patients with
either nephrotoxicity or ototoxicity caused by an aminoglycoside antibi-
otic. Supportive care is the mainstay of therapy. Experimental treatments in
animal models include the use of deferoxamine, glutathione, and NMDA
receptor antagonists in an attempt to chelate and/or detoxify a reactive
intermediate. 181, 231 The antibiotic ticarcillin forms a renally eliminated
complex with aminoglycosides in the blood to provide protection against
tobramycin-induced renal toxicity. In humans, ticarcillin removes 50%
more tobramycin in 48 hours than two hemodialysis sessions.
79 However,
ticarcillin therapy is generally of limited value because in most instances
TABLE 56–2. Antimicrobial Pharmacokinetics
Volume of
Xenobiotic Absorption Distribution (L/kg) Elimination Route t1/2 (h)
Antibacterial
Aminoglycosides Parenteral 0.25 Renal 2–3
Penicillins, Oral, parenteral Variable Renal (predominant) Variable
cephalosporins, and
other β-lactams
Chloramphenicol Oral, parenteral, otic 0.5–1.0 90% hepatic, 10% renal 1.6–3.3
Fluoroquinolones Oral, parenteral Variable Renal 3–5
Ketolides Oral 2.9 L/kg 63% renal, 37% hepatic 10–13
(50% of which is CYP3A4)
Macrolides Oral, parenteral Variable Hepatic Variable
Sulfonamides Oral, parenteral Variable Hepatic Variable
Tetracyclines Oral Variable Hepatic 6–26
Vancomycin Parenteral 0.2–1.25 Renal 4–6
Antifungal
Triazoles and imidazoles Oral Variable Hepatic Variable
Amphotericin B Parenteral 4.0 Hepatic 360
Antiviral
Acyclovir Parenteral, oral, topical 0.8 Renal 2.2–20
TABLE 56–3. Predominant Aminoglycoside Toxicity
Cochlear and
Cochlear Vestibular Vestibular Renal
Kanamycin Amikacin Streptomycin Amikacin
Neomycin Gentamicin Gentamicin
Tobramycin Kanamycin
Neomycin
Streptomycin
Tobramycin
glutamate activated N -methyl-D-aspartate (NMDA) receptors may
play a role.
108, 253 The incidence of nephrotoxicity with aminoglycoside
therapy is estimated at 5% to 10%.
9 Although the aminoglycosides are
almost completely excreted prior to biotransformation in the kidney,
a small fraction of filtered aminoglycoside is transported by absorp-
tive endocytosis across the apical membrane of proximal tubular cells
where it becomes sequestered within lysosomes. The aminoglycoside
then binds to and destroys phospholipids contained on brush border
membranes in the proximal renal tubule.
9
When this happens, acute tubular necrosis occurs after 7 to 10 days
of standard-dose therapy. Laboratory abnormalities include granular
casts, proteinuria, elevated urinary sodium, and increased fractional
excretion of sodium. Usually renal dysfunction is reversible; however,
irreversible toxicity is reported. Functional renal injury occurs days
prior to elevations in serum creatinine concentration, and for this rea-
son a delay in diagnosis is common.
217 Risk factors for the development
of nephrotoxicity include increasing age, renal dysfunction, female sex,
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820 Part C The Clinical Basis of Medical Toxicology
the serum concentration of the aminoglycoside has decreased before any
therapeutic measures can be used. The use of ticarcillin should be consid-
ered only early after large overdose in patients with either demonstrated
toxicity or renal failure where the risks of toxicity are significant.
PENICILLINS
Penicillin nucleus
N
SCH3
CH3
COOH
NHC
O
R
O
Penicillin is derived from the fungus Penicillium and many semisyn-
thetic derivatives have clinical utility. Penicillins, as a class, contain
a 6-aminopenicillanic acid nucleus, composed of a β-lactam ring
fused to a five-member thiazolidine ring. Classic available penicillins
include penicillin G, penicillin V, and the antistaphylococcal penicillins
(nafcillin, oxacillin, cloxacillin, and dicloxacillin). Penicillins developed
to enhance the spectrum of antibiotic efficacy, particularly against
gram-negative bacilli, include the second-generation penicillins (ampicillin,
amoxicillin, bacampicillin, and mezlocillin), third-generation penicillins
(carbenicillin and ticarcillin), and fourth-generation penicillins
(piperacillin).
Table 56–1 lists the pharmacologic mechanism of peni-
cillins and
Table 56–2 lists their pharmacokinetic properties.
Acute oral overdoses of penicillin-containing drugs are usually not
life threatening.
237 The most frequent complaints following acute over-
dose are nausea, vomiting, and diarrhea.
Seizures occur in persons given large intravenous or intraventricular
doses of penicillins.
40, 127, 139, 164 More than 50 million units intravenously
in less than 8 hours are generally required to produce seizures in
adults. 222 Penicillin-induced seizures appear to be mediated through
an interaction of the drug with the picrotoxin-binding site on the neu-
ronal chloride channel near the γ-aminobutyric acid (GABA) binding
site (Chap. 13). Binding of the penicillin produces an allosteric change
in the receptor that prevents GABA from binding, resulting in a rela-
tive lack of inhibitory tone.
66 Penicillin analogs (such as imipenem) also
cause seizures, presumably through a similar mechanism.
Treatment of patients who develop penicillin-induced seizures
include GABA agonists such as the benzodiazepines and barbiturates,
if needed. Patients who receive an intraventricular overdose may
require cerebrospinal fluid exchange or perfusion to attenuate seizure
activity (see Special Considerations SC 2: Intrathecal Administration
of Xenobiotics).
139 There are rare reports of hyperkalemia resulting in
electrocardiographic abnormalities after the rapid intravenous infusion
of potassium penicillin G to patients with renal failure and amoxicillin
overdose resulting in frank hematuria and renal failure.
37,94 There is
also a single case report of penicillin-associated hearing loss.
33
Adverse Effects Associated With Therapeutic Use Penicillins are associ-
ated with a myriad of adverse effects after therapeutic use, the most
common of which are allergic reactions. Penicillins are commonly
implicated in immune-related reactions such as bone marrow suppres-
sion, cholestasis, hemolysis, interstitial nephritis, and vasculitis.
6, 92, 114, 230
Rare effects include pemphigus after penicillin use and corneal damage
after the use of methicillin.
23, 263
Acute Allergy Penicillins are the pharmaceuticals most commonly
implicated in the development of acute anaphylactic reactions.
Anaphylactic reactions are severe life-threatening immune-mediated
(IgE) reactions involving multiple organ systems that occur most often
immediately after exposure to a trigger.
Table 56–4 lists the classifica-
tions of anaphylactic reactions. Anaphylaxis to penicillin typically
occurs after IgE antibody formation, which requires prior exposure.
Life-threatening clinical manifestations include angioedema, tongue
and airway swelling, bronchospasm, bronchorrhea, dysrhythmias,
cardiovascular collapse, and cardiac arrest.
80 The pathophysiology of
systemic anaphylaxis is complex and involves multiple pathways. IgE
antibodies are cross-linked on the surface of mast cells and basophils,
resulting in local and systemic release of preformed mediators of
anaphylactic response, including leukotrienes C
4 and D
4 , histamine,
eosinophilic chemotactic factor, and other vasoactive substances, such as
bradykinin, kallikrein, prostaglandin D
2 , and platelet-activating
factor.
The incidence of penicillin hypersensitivity is 5% overall, with 1% of
penicillin reactions resulting in anaphylaxis. The risk for a fatal hypersen-
sitivity reaction after penicillin administration is two per 100,000 (0.002%)
patient exposures.
251 All routes of penicillin administration can result
in anaphylaxis; however, it occurs most commonly after intravenous
administration.
Treatment is supportive with careful attention to airway, breathing,
and circulation. If the penicillin was ingested, the patient may theo-
retically benefit from oral activated charcoal 1 g/kg. This is unlikely
to prevent anaphylaxis, as only a few molecules need be absorbed to
trigger the immunologic response. Initial drug therapy for anaphylaxis
includes epinephrine 0.01 mg/Kg (up to 0.5 mL) of 1:1000 dilution
subcutaneously (SC) every 10 to 20 minutes. Through β-receptor
stimulation, epinephrine bronchodilates and increases cardiac output.
In addition, β-receptor stimulation results in decreased peripheral vas-
cular tone. Oxygen and inhaled β
2 -adrenergic agonists are warranted
in severe cases, as are corticosteroids. H
1 -receptor antagonists may
be sufficient in patients with mild allergic reactions who do not have
pulmonary manifestations or airway concerns.
H 2 -receptor antagonism as a treatment for anaphylaxis is contro-
versial. H
2 -receptors, when stimulated in the peripheral vasculature,
cause vasodilation; in the heart, they cause positive inotropy, positive
chronotropy, and coronary vasodilation; and in the lung, they cause
increased mucus production.
212 Theoretically, H 2 -receptor antagonists
can lead to a decrease in myocardial activity at a time when H
1 -receptor
stimulation is causing hypotension, coronary vasoconstriction, and
bronchospasm. However, in vitro and animal models demonstrate
decreases in coronary circulation and decreases in the overall anaphy-
lactic response following administration of H
1 blockers. 16, 27 Cimetidine
and ranitidine are useful for the treatment of pruritus and flushing
after acute allergic reactions involving the skin.
154, 168 Cimetidine use
following anaphylaxis may result in clinical improvement, particu-
larly hypotension and tachycardia.
72, 264 There is one case, however, of
chronic ranitidine administration, which was postulated to result in
heart block after an anaphylactic response to latex.
189 Available data
indicate that treatment using H
2 -receptor antagonists should only be
TABLE 56–4. Classification of Anaphylactic Reactions
Grade Description
I Large local contiguous reaction (>15 cm)
II Pruritus (urticaria) generalized
III Asthma, angioedema, nausea, vomiting
IV Airway (asthma, lingual swelling, dysphagia, respiratory
distress, laryngeal edema)
Cardiovascular (hypotension, cardiovascular collapse)
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Chapter 56 Antimicrobials, Antifungals, and Antivirals
considered when other therapies have failed and the patient is ade-
quately H
1 -receptor blocked. Aminophylline, although mentioned in
some references for the treatment of anaphylaxis, is inadequately stud-
ied and should not be routinely used. Finally, glucagon may be of some
benefit, particularly in patients who are maintained on β-adrenergic
antagonists (Chap. 61 and A-19).
Amoxicillin-Clavulanic Acid and Hepatitis Cholestatic hepatitis occurs
1 to 6 weeks after initiation of therapy with amoxicillin-clavulanate.
7
The incidence of hepatotoxicity typically is estimated at 1.1 to
2.7 per 100,000 prescriptions.
91 The mechanism of hepatotoxicity is
not clear, but may be related to clavulanate, a β-lactamase inhibitor
used to prevent the bacterial destruction of β-lactam antimicrobials,
or one of its metabolites. Treatment is supportive and clinical find-
ings typically resolve after the discontinuation of therapy. However,
prolonged hepatitis, ductopenia (vanishing bile duct syndrome), and
pancreatitis rarely occur.
53, 199 Behavorial disturbance with disorienta-
tion, agitation, and visual hallucinations is also reported temporally
related to use.
19
Hoigne Syndrome and Jarisch-Herxheimer Reaction The most common
adverse effects occurring after administration of large intramuscular or
intravenous doses of procaine penicillin G are the Hoigne syndrome
and the Jarisch-Herxheimer reaction.
12, 90, 102, 122, 163 Hoigne syndrome
is characterized by extreme apprehension and fear, illusions, or hal-
lucinations; changes in auditory and visual perception; tachycardia;
systolic hypertension; and, occasionally, seizures that begin within
minutes of injection.
250 These effects occur in the absence of signs or
symptoms of anaphylaxis. The cause of this syndrome is unknown.
Procaine is implicated as the causative agent because of this syndrome’s
similarity to events that occur after the administration of other phar-
macologically similar local anesthetics.
214, 223, 246 Hoigne syndrome is
six times more common in men than women.
226 The reason for this
increased prevalence is unclear, but autosomal dominance and influ-
ences of prostaglandin and thromboxane A
2 activity in this population
may be responsible.
12
The Jarisch-Herxheimer reaction is a self-limited reaction that
develops within a few hours of antibiotic therapy for the treatment
of early syphilis or Lyme disease. Clinical findings include myalgias,
chills, headache, rash, and fever, which spontaneously resolve within
18 to 24 hours, even with continued antibiotic therapy.
169 The patho-
genesis of this reaction is likely an acute antigen release by lysed
bacteria. 178
CEPHALOSPORINS
Cephem nucleus
N
S
R
2
COOH
O
NHC
O
R
1
Cephalosporins are semisynthetic derivatives of cephalosporin C pro-
duced by the fungus Acremonium, previously called Cephalosporium .
Cephalosporins have a ring structure similar to that of penicillins.
Cephalosporins are generally divided into first, second, third, and
fourth generations based on their antimicrobial spectrum. First-
generation cephalosporins include cefadroxil, cefazolin, cephalexin,
cephapirin, and cephradine. Second-generation cephalosporins include
cefaclor, cefamandole, cefonicid, cefotetan, cefoxitin, cefprozil, and
cefuroxime. Third-generation cephalosporins include cefdinir, cef-
tazidime, cefixime, ceftibuten, cefoperazone, ceftizoxime, cefotaxime,
ceftriaxone, and cefpodoxime. Finally, of the fourth-generation cepha-
losporins, cefepime was the first to be marketed.
Effects occurring after acute overdose of cephalosporins resemble
those occurring after penicillin exposure. Some cephalosporins also
have epileptogenic potential similar to penicillin.
255 Case reports demon-
strate seizures after inadvertent intraventricular administration.
39, 146, 265
Management of cephalosporin overdose is similar to that of penicillin
overdose.
Table 56–1 lists the pharmacologic mechanism of cepha-
losporins and
Table 56–2 lists their pharmacokinetic properties.
Adverse Effects Associated With Therapeutic Use Cephalosporins
rarely cause an immune-mediated acute hemolytic crisis.
78 Cefaclor
is the cephalosporin most commonly reported to cause serum sick-
ness, although this can occur with other cephalosporins.
132, 156 Also like
penicillins, first-generation cephalosporins are associated with chronic
toxicity, including interstitial nephritis and hepatitis.
262 Cefepime is
reported in a single case to cause reversible coma and electroencepha-
logram (EEG) confirmed nonconvulsive seizures.
2
Cross-Hypersensitivity The cephalosporins contain a six-member
dihydrithiazine ring instead of the five-member thiazolidine penicil-
lin ring. The extent of cross-reactivity between penicillins and cepha-
losporins in an individual patient is largely determined by the type of
penicillin allergic response experienced by the patient. The incidence
of anaphylaxis to cephalosporins is between 0.0001% and 0.1%, with
a threefold increase in patients with previous penicillin allergy.
133
Ten percent of patients with prior penicillin-related anaphylactic
reactions will have positive skin test for cephalosporin hypersensi-
tivity. 205 A negative skin test predicts a negative allergic response on
oral cephalosporin challenge in penicillin-allergic patients. Finally,
the incidence of delayed hypersensitivity reactions after cepha-
losporin use is 1% to 2.8% in the general population and 8.1% in
those with prior penicillin delayed hypersensitivity. Cross-reactivity
may be greater with the first- and second-generation cephalosporins
that are more structurally similar to penicillin or that are contami-
nated by penicillin.
8 Antibody binding after cephalosporin exposure
occurs at the determinants located on the side-chain groups of the
cephalosporin. 14 In fact, IgE directed against a methylene substitu-
ent linking the side chain to the penicillin molecule is identified.
107
These determinants are quite distinct among cephalosporins, which
cause the pattern of cross-hypersensitivity among cephalosporins
to be much less well defined than among the penicillins. Caution
should be used when considering cephalosporins in penicillin- or
cephalosporin-allergic patients; however, if a risk-to-benefit analysis
demonstrates a clear benefit to the patient without equivalent alterna-
tives, the cephalosporin should be given.
N -methylthiotetrazole Side-Chain Effects Cephalosporins containing
an N -methylthiotetrazole (nMTT) side chain (moxalactam, cefazolin,
cefoperazone, cefmetazole, cefamandole, cefotetan) have toxic effects
unique to their group structure. As these cephalosporins undergo
metabolism, they release free nMTT, which is responsible for their
effects (
Fig. 56–1 ). 165 Free nMTT inhibits the enzyme aldehyde dehy-
drogenase and, in conjunction with ethanol, can cause a disulfiram-like
reaction (Chap. 79).
43
The nMTT side chain is also associated with hypoprothrombine-
mia, although a causal relationship is controversial.
101 It is thought that
nMTT depletes vitamin K-dependent clotting factors by inhibition
of vitamin K epoxide reductase.
183 In a study of children 1 month to
1 year of age who were maintained on a prolonged antibiotic regimen,
a significant degree of vitamin K depletion was found.
25 Treatment of
patients suspected of hypoprothrombinemia caused by these cepha-
losporins consists of fresh-frozen plasma, if bleeding is evident, and
vitamin K
1 in doses required to resynthesize vitamin K cofactors
(Chap. 59).
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822 Part C The Clinical Basis of Medical Toxicology
OTHER β-LACTAM ANTIMICROBIALS
Imipenem
S
N
H2N
N
N
N
SO3H
CH3
H
O
HOOC
CH3
CH3
O
O
Aztreonam
N
COOH
O
S
C
HO
H
HH
NNH
H3C
Included in this group are monobactams such as aztreonam and car-
bapenems such as imipenem and meropenem.
Table 56–1 lists the
pharmacologic mechanism of these drugs, and
Table 56–2 lists their
pharmacokinetic properties.
Effects occurring after acute overdose of other β-lactam antimicro-
bials resemble those occurring after penicillin exposure. Imipenem
has epileptogenic potential in both overdose and therapeutic dosing
(see section Adverse Effects Associated With Therapeutic Use).
48, 148
Management guidelines for other β-lactam overdoses are similar to
those for penicillin overdoses.
Adverse Effects Associated With Therapeutic Use The risk factors for
imipenem-related seizures include central nervous system disease, prior
seizure disorders, and abnormal renal function.
190 The mechanism for
seizures appears to be GABA antagonism (similar to the penicillins) in
conjunction with enhanced activity of excitatory amino acids.
67, 235
Cross-Hypersensitivity Aztreonam is a monobactam that does not
contain the antigenic components required for cross-allergy with peni-
cillins, and generalized cross-allergenicity is not expected.
215 However,
aztreonam cross-reacts in vitro with ceftriaxone, thought to be the result
of the similarity in their side-chain structure.
192 Cross-allergenicity has
also been noted between imipenem and penicillin, although the inci-
dence has yet to be determined.
TRIMETHOPRIM-SULFAMETHOXAZOLE
Trimethoprim and sulfamethoxazole work as antibacterials in tandem
effectively preventing tetrahydrofolic acid synthesis in bacterial cells.
Significant toxicity after acute overdose is not expected; however, a
myrid of effects occur after chronic therapeutic use. Trimethoprim/
sulfamethoxazole combinations are commonly reported to result in
cutaneous allergic reactions, hematologic disorders, methemoglobin-
emia, hypoglycemia, rhabdomyolysis, and psychosis.
134, 135, 234, 254, 260
CHLORAMPHENICOL
O2NCHCHNHCCH
H2C
OH
O
Cl
Cl
OH
Chloramphenicol was originally derived from Streptomyces venezuelae and
is now produced synthetically. Antimicrobial activity exists against many
gram-positive and gram-negative aerobes and anaerobes.
Table 56–1 lists
the pharmacologic mechanism of chloramphenicol, and
Table 56–2
lists its pharmacokinetic properties.
Acute overdose of chloramphenicol commonly causes nausea and vom-
iting. Effects are caused by its ability to inhibit protein synthesis in rapidly
proliferating cells. Metabolic acidosis occurs as a result of the inhibition
of mitochondrial enzymes, oxidative phosphorylation, and mitochondrial
biogenesis. 88 Infrequently, sudden cardiovascular collapse can occur 5 to
12 hours after acute overdoses. In case series, cardiovascular compromise
was more frequent in patients with serum concentrations greater than
50 μg/mL. 88, 172, 242 Because concentrations are not readily available, all
poisoned patients should be closely observed for at least 12 hours after expo-
sure. Orogastric lavage may be useful for recent ingestions when the patient
has not vomited, and activated charcoal 1 g/kg should be given orally.
Extracorporeal means of eliminating chloramphenicol are not
usually required because of its rapid metabolism (see
Table 56–2 ).
However, both hemodialysis and charcoal hemoperfusion decrease ele-
vated serum chloramphenicol concentrations and may be of benefit in
patients with large overdoses, or in patients with severe hepatic or renal
dysfunction. 87, 167, 227 Exchange transfusion also lowers chloramphenicol
serum concentrations in neonates.
233 Surviving patients should be
closely monitored for signs of bone marrow suppression.
Adverse Effects Associated With Therapeutic Use Chronic toxicity
of chloramphenicol is similar to that which occurs following acute
poisoning. The classic description of chronic chloramphenicol toxicity
is the “gray baby syndrome.”
87, 88, 167, 233 Children with this syndrome
exhibit vomiting, anorexia, respiratory distress, abdominal disten-
sion, green stools, lethargy, cyanosis, ashen color, metabolic acidosis,
hypotension, and cardiovascular collapse.
The majority (90%) of a dose of chloramphenicol is metabolized via
glucuronyl transferase, forming a glucuronide conjugate. The remainder
is excreted renally unchanged. Infants, in particular, are predisposed to
the gray baby syndrome because they have a limited capacity to form a
glucuronide conjugate of chloramphenicol and, concomitantly, a limited
ability to excrete unconjugated chloramphenicol in the urine.
97, 261
CH2CH3
H3C
CH2C NH
OC
CH
C
O
O
OCOOH
SN
S
CH2
CH C
OH
Cephalothin (without side chain)
Cefamandole (with side chain)
NH
S
CH
C
O
OCOOH
N
S
NN
N
N
nMTT side chain
H3C
SNN
N
N
FIGURE 56-1. Characteristic structures of cephalosporins emphasizing the nMTT
side chain.
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823
Chapter 56 Antimicrobials, Antifungals, and Antivirals
There are two types of bone marrow suppression that occur after
use of chloramphenicol. The most common type is dose dependent
and occurs with high serum concentrations of chloramphenicol.
118, 119, 221
Clinical manifestations usually occur within several weeks of therapy
and include anemia, thrombocytopenia, leukopenia, and very rarely,
aplastic anemia. Bone marrow suppression is generally reversible on
discontinuation of therapy. A second type of bone marrow suppression
caused by chloramphenicaol occurs through this inhibition of protein
synthesis in the mitochondria of marrow cell lines.
175 This type causes
the development of aplastic anemia, which is not dose related and gener-
ally occurs in susceptible patients within 5 months of treatment and has
an approximately 50% mortality rate (Chap. 24).
77, 268 The dehydro and
nitroso bacterial metabolites of chloramphenicol injure human bone
marrow cells through inhibition of myeloid colony growth, inhibition of
DNA synthesis, and inhibition of mitochondrial protein synthesis.
129
Other adverse effects associated with chloramphenicol include
peripheral neuropathy
195 ; neurologic abnormalities, such as confu-
sion and delirium
150 ; optic neuritis 59 ; nonlymphocytic leukemia 225 ; and
contact dermatitis. 140
FLUOROQUINOLONES
Ciprofloxacin
N
O
COOH
F
N
HN
The fluoroquinolones are a structurally similar, synthetically derived
group of antimicrobials that have diverse antimicrobial activities. They
include balofloxacin, ciprofloxacin, clinafloxacin, enoxacin, fleroxacin,
gatifloxacin, gemifloxacin, grepafloxacin, levofloxacin, lomefloxacin,
moxifloxacin, nadifloxacin, nalidixic acid, norfloxacin, ofloxacin,
pefloxacin, rufloxacin, sparfloxacin, temafloxacin, tosufloxacin, and
trovafloxacin. Like other antimicrobials, the fluoroquinolones rarely
produce life-threatening effects following acute overdose, and most
patients can be safely managed with minimal intervention.
11 Table 56–1
lists the pharmacologic mechanism of fluoroquinolones, and
Table 56–2
lists their pharmacokinetic properties.
Rarely, acute overdose of a fluoroquinolone results in renal failure
or seizures.
143 The mechanism of renal failure after fluoroquinolone
exposure is controversial. In animals, ciprofloxacin and norfloxacin
cause nephrotoxicity, especially in the setting of neutral or alkaline
urine. 61, 218 In humans, renal failure is reported after both acute and
chronic exposure to fluoroquinolones. A hypersensitivity reaction is
postulated to explain pathologic changes consistent with interstitial
nephritis. 116, 202 Treatment includes discontinuation of the fluoroqui-
nolone and supportive care. Improvement in renal function is usually
noticed within several days.
Seizures are reported with ciprofloxacin and may be a result of the
inhibition of GABA.
228, 245 Others postulate that seizures result from the
ability of fluoroquinolones to bind efficiently to cations, particularly
magnesium. This hypothesis is related to the inhibitory role of mag-
nesium at the excitatory NMDA-gated ion channel (Chap. 13).
68, 219
Treatment is supportive, using benzodiazepines and, if necessary,
barbiturates to increase inhibitory tone.
Adverse Effects Associated With Therapeutic Use Several fluoroquinolo-
nes are substrates and/or inhibitors of cytochrome CYP isozymes. This
can result in drug interactions, which are especially important with
drugs that have a narrow therapeutic index.
Serious adverse effects related to fluoroquinolone use consist of
central nervous system toxicity, as discussed, cardiovascular toxicity,126
hepatotoxicity, and notable musculoskeletal toxicity.
Fluoroquinolones cause prolongation of the QT interval and may cause
torsades de pointes.
40, 126,213 Although the mechanism is unclear, sequester-
ing of magnesium, resulting in clinical hypomagnesemia, is postulated.
219
Treatment of patients presenting with QT prolongation is supportive,
with careful attention to magnesium supplementation if necessary.
The fluoroquinolones rarely result in potentially fatal
hepatotoxicity. 54, 89, 99, 144, 158, 206 This adverse effect is most notable with
trovafloxacin. In vitro models show trovafloxacin to be uniquely capa-
ble of altering gene expression that regulates oxidative stress and RNA
processing leading to mitochondrial damage.
152 Consequently, trova-
floxacin (Trovan) is now reserved only for the treatment of patients
with life-threatening infections in whom the benefits are thought to
outweigh the risks. In addition, the manufacturer has initiated a lim-
ited distribution system that allows drug shipment only to pharmacies
within inpatient healthcare facilities.
Fluoroquinolones should be used with caution in children and
pregnant women because of their potential adverse effects on develop-
ing cartilage and bone. Damage to articular cartilage is demonstrated
in young dogs and rats, although the extent varies among different
fluoroquinolones. 45, 238 There are very limited data regarding damage to
articular cartilage as a result of using fluoroquinolones in humans; how-
ever, children given ciprofloxacin on a compassionate basis developed
complaints of swollen, painful, and stiff joints after 3 weeks of therapy.
128
All signs and symptoms abated within 2 weeks of discontinuation of
therapy. However, 29 additional children treated with ofloxacin or
ciprofloxacin showed no differences with respect to cartilage thick-
ness, cartilage structure, edema, cartilage-bone borderline, or synovial
fluid.65 Women who received quinolones during pregnancy had larger
babies and more caesarean deliveries because of fetal distress than did
controls. 22 However, there were no congenital malformations, delay to
developmental milestones, or musculoskeletal abnormalities found.
Fluoroquinolones are also implicated as a cause of tendon rupture,
which is reported to occur up to 120 days after the start of treatment
and even after the discontinuation of therapy.
191 The fluoroquinolone
should be discontinued in patients, particularly athletes who complain
of symptoms consistent with painful and swollen tendons.
Other adverse effects include acute psychosis, dysglycemia (hyper-
and hypoglycemia), rash, tinnitus, eosinophilia, serum sickness, and
photosensitivity. 44, 103, 173, 188, 232
MACROLIDES AND KETOLIDES
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824 Part C The Clinical Basis of Medical Toxicology
The macrolide antimicrobials include various forms of erythromycin
(base, estolate, ethylsuccinate, gluceptate, lactobionate, stearate),
azithromycin, clarithromycin, troleandomycin, and dirithromycin.
Ketolides are similar in pharmacology to macrolides; telithromycin is
the only available agent at this time.
Table 56–1 lists the pharmacologic
mechanism of macrolides and ketolides, and
Table 56–2 lists their
pharmacokinetic properties.
Acute oral overdoses of macrolide antimicrobials are usually not
life threatening and symptoms, which are generally confined to the
gastrointestinal tract, include nausea, vomiting, and diarrhea. A single
case of pancreatitis is reported.
241 Erythromycin lactobionate causes
QT prolongation and torsades de pointes after intravenous use.
184
Oral erythromycin is also implicated in causing prolongation of the
QT and torsades de pointes, especially in patients concurrently taking
cytochrome P450 (CYP) 3A4 inhibitors.
196 In vitro models demon-
strate erythromycin’s ability to slow repolarization in a concentration-
dependent manner.
177 The cause of prolonged QT interval was once
thought to be from hypokalemia-induced promotion of intracellular
efflux of potassium.
197 Data, however, demonstrate that the QT interval
prolongation results from blockade of delayed rectifier potassium cur-
rents (Chaps. 22 and 23).
208 QT prolongation and torsades de pointes
are common after intravenous erythromycin lactobionate.
184 More pro-
nounced prolongation occurs in patients with underlying heart disease
and correlates with the infusion rate.
106 Epidemiologic studies note an
increased incidence of ventricular dysrhythmias in women treated with
erythromycin. 75
Although there are no acute overdose data regarding ketolide
antimicrobials, effects are expected to be similar to macrolide anti-
microbials. Therapeutic use of telithromycin is reported to result
in QT prolongation, hepatotoxicity, toxic epidermal necrolysis and
anaphylaxis. 1, 17, 27,29, 74, 185
Adverse Events Associated With Therapeutic Use Drug Interactions.
Erythromycin is the prototypical macrolide and, as such, has received
the most attention with respect to potential and documented drug
interactions. 115 Clarithromycin, erythromycin, and troleandomycin are
all potent inhibitors of the CYP3A4 enzyme system; azithromycin does
not inhibit this enzyme.
64 Erythromycin inhibits cytochrome P450 after
metabolism to a nitroso intermediate, which then forms an inactive
complex with the iron (II) of cytochrome P450. Chapter 12 (Appendix)
lists substrates for the CYP3A4 system. Clinically significant interactions
occur with erythromycin and warfarin, carbamazepine, terfenadine
or cyclosporine.
46, 111,115, 194 Inhibition of cisapride metabolism results in
increased concentrations of the parent drug, which is capable of caus-
ing prolongation of the QT interval and causing torsades de pointes.
35
Cases of carbamazepine toxicity are documented when combined with
the use of erythromycin.
111 Erythromycin also inhibits CYP1A2, produc-
ing clinically significant interactions with clozapine, theophylline, and
warfarin. 204
Macrolides may also interact with the absorption and renal excretion
of drugs that are amenable to intestinal P-glycoprotein excretion, or
interfere with normal gut flora responsible for metabolism. This may
be part of the underlying mechanism of cases of macrolide-induced
digoxin toxicity (Chap. 64).
182
End-Organ Effects The most common toxic effect of macrolides after
chronic use is hepatitis, which may be immune mediated.
49 Erythromycin
estolate is the agent most frequently implicated in causing cholestatic
hepatitis. 96, 123
Large doses (more than 4 g/d) of macrolide antimicrobials are
also associated with reversible high-frequency sensorineural hearing
loss. 41 Renal impairment may be a risk factor.
211, 236 There are rare case
reports in which ototoxicity did not resolve following discontinua-
tion of therapy.
149 There are insufficient data concerning the ototoxic
potential of the other macrolide antimicrobials. Other, rare toxic effects
associated with macrolides include cataracts after clarithromycin use
in animals and acute pancreatitis in humans.
82, 249 Allergy is rare and
reported at a rate of 0.4% to 3%.
70 Telithromycin contains a carbamate
side chain that may interfere with the normal function of neuronal
cholinesterase. It should be used cautiously in patients with myasthenia
gravis, particularly patients receiving pyridostigmine because of the
risk of cholinergic crisis.
240
Clindamycin is a lincosamide with similar structure and clinical
effects to macrolides. Clindamycin phosphate is commonly used
topically while clindamycin hydrochloride is available for intravenous
use. Data regarding acute overdose is limited and the majority of the
chronic toxicity is seen after use of systemic doses of clindamycin
phosphate. The most consequental toxicity is gastrointestinal resulting
in esophageal ulcers, diarrhea, and colitis.
203
SULFONAMIDES
Sulfamethoxazole
ON
H2N
S
OO
NH CH3
Sulfonamides antagonize para -aminobenzoic acid or para- aminobenzyl
glutamic acid, which are required for the biosynthesis of folic acid.
Table 56–1 lists the pharmacologic mechanism of sulfonamides, and
Table 56–2 lists their pharmacokinetic properties. Acute oral overdoses
of sulfonamides are usually not life threatening, and symptoms are
generally confined to nausea, although allergy and methemoglobinemia
occur rarely.
86 Treatment is similar to acute oral penicillin overdoses.
Adverse Effects Associated With Therapeutic Use The most common
adverse effects associated with sulfonamide therapy are nausea and
cutaneous hypersensitivity reactions. Hypersensitivity reactions are
thought to be caused by the formation of hapten sulfamethoxazole
metabolites, N -hydroxy-sulfamethoxazole and nitroso-sulfamethoxazole.
The degree of hapten binding is mitigated in vitro by cysteine and
glutathione. 176 The incidence of adverse reactions to sulfonamides,
including allergy, is increased in HIV-positive patients and is positively
correlated to the number of previous opportunistic infections experi-
enced by the patient.
147 This may be caused by a decrease in the mecha-
nisms available for detoxification of free radical formation, as cysteine
and glutathione levels are low in these patients.
257 Whether supplemen-
tation with a glutathione precursor such as N -acetylcysteine will reduce
the incidence of these reactions is unknown.
3
Methemoglobinemia and hemolysis also rarely occur.
76, 155 The mech-
anism for adverse reactions is not entirely clear. However, when sul-
famethoxazole is exposed to ultraviolet B (UVB) radiation in vitro, free
radicals are formed that can participate in the development of tissue
peroxidation and hemolysis.
268 This finding may be of particular impor-
tance in treating patients with glucose-6-phosphate dehydrogenase
(G6PD) deficiency associated with decreased in reducing capabilities.
5
The sulfonamides are associated with many chronic adverse effects.
Bone marrow suppression is rare, but the incidence is increased in
patients with folic acid or vitamin B 12 deficiency, and in children,
pregnant women, alcoholics, dialysis patients, and immunocompro-
mised patients, as well as in patients who are receiving other folate
antagonists. Other adverse effects include hypersensitivity pneumoni-
tis, stomatitis, aseptic meningitis, hepatotoxicity, renal toxicity, and
central nervous system toxicity.
30
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825
Chapter 56 Antimicrobials, Antifungals, and Antivirals
TETRACYCLINES
Tetracycline
OH O OH
OH
O
C
NH2
O
OH
N
H3CCH
3
HO CH3
Tetracyclines are derivatives of Streptomyces cultures. Currently avail-
able tetracyclines include demeclocycline, doxycycline, methacycline,
minocycline, oxytetracycline, and tetracycline.
Table 56–1 lists the
pharmacologic mechanism of tetracyclines, and
Table 56–2 lists their
pharmacokinetic properties. Significant toxicity after acute overdose of
tetracyclines is unlikely. Gastrointestinal effects consisting of nausea,
vomiting, and epigastric pain have been reported.
42
Adverse Effects Associated With Therapeutic Use Tetracycline should
not be used in children during the first 6 to 8 years of life or by preg-
nant women after the 12th week of pregnancy because of the risk of
development of secondary tooth discoloration in children or developing
children in utero.
Other effects associated with tetracyclines include nephrotoxicity,
hepatotoxicity, skin hyperpigmentation in sun-exposed areas, and
hypersensitivity reactions.
49, 100, 121, 239 More severe hypersensitivity
reactions, drug-induced lupus, and pneumonitis are reported after
minocycline use, as are cases of necrotizing vasculitis of the skin
and uterine cervix, and lymphadenopathy with eosinophilia.
160, 220, 224
Demeclocycline rarely causes nephrogenic diabetes insipidus (Chap. 16).50
Of historical interest, outdated older formulations of tetracycline were
reported to cause hypouricemia, hypokalemia, and a proximal and
distal renal tubular acidosis.
57
VANCOMYCIN
Vancomycin
H3C
CH3
O
CH3
NH2
H3C
HO
O
O
OH OH
CH2OH
O
OO
Cl
Cl
NN
O
O
N
O
HOOC
H
HO OH
H
N
N
O
ONH
2
H
O
OH
H
N
O
NHCH3
H
H
OH
H
H
HO
Vancomycin is obtained from cultures of Nocardia orientalis and is a tri-
cyclic glycopeptide. Vancomycin is biologically active against numerous
gram-positive organisms.
Table 56–1 lists the pharmacologic mechanism
of vancomycin, and
Table 56–2 lists its pharmacokinetic properties.
Acute oral overdoses of vancomycin rarely cause significant toxicity
and most cases can be treated with supportive care alone. Multiple-dose
activated charcoal and potentially high-flux hemodialysis can be con-
sidered for patients with large overdoses when the patient is expected
to have prolonged clearance.
141, 248
Adverse Effects Associated With Therapeutic Use Patients who receive
intravenous vancomycin may develop the “red man syndrome” through
an anaphylactoid reaction.
93 Symptoms include chest pain, dyspnea,
pruritus, urticaria, flushing, and angioedema.
207 Signs and symptoms
spontaneously resolve, typically within 15 minutes. Other symptoms
attributable to red man syndrome include hypotension, cardiovascular
collapse, and seizures.
13, 179
The incidence of red man syndrome appears to be related to the
rate of infusion and is approximately 14% when 1 g is given over
10 minutes, whereas it is 3.4% when given over 1 hour.
179, 186 A trial in
11 healthy persons studied the relationship between intradermal skin
hypersensitivity and the development of red man syndrome. Each of the
11 subjects underwent skin testing that was followed 1 week later by an
intravenous dose of vancomycin 15 mg/kg over 60 minutes. Following
intravenous vancomycin, all subjects developed dermal flare responses
and erythema, and 10 of 11 subjects developed pruritus within 20 to 45
minutes. After the infusion was terminated, symptoms resolved within
60 minutes.
193
The signs and symptoms of red man syndrome are related to the rise
and fall of histamine concentrations.
110, 151 Tachyphylaxis occurs in patients
given multiple doses of vancomycin.
109, 256 Animal models demonstrated a
direct myocardial depressant and vasodilatory effect of vancomycin.
60
More serious reactions result when vancomycin is given via intravenous
bolus, further supporting a rate-related anaphylactoid mechanism.
24
Patients most often experience red man syndrome after vancomy-
cin is administered intravenously. In rare cases, oral administration
of vancomycin can also result in the syndrome.
21 Treatment includes
increasing the dilution of vancomycin and slowing intravenous admin-
istration. Antihistamines may be useful as pretreatment, especially prior
to the first dose.
198 A placebo-controlled trial in adult patients studied
the incidence of these symptoms in patients given 1 g of vancomycin
over 1 hour, as well as the effect of diphenhydramine in the prevention
of the syndrome.
256 There was a 47% incidence of reaction without
diphenhydramine and a 0% incidence with diphenhydramine.
Chronic use of vancomycin may cause reversible nephrotoxicity,
particularly in patients with prolonged excessive steady-state se rum
levels. 10, 201 Concomitant administration of aminoglycoside antimi-
crobials may increase the risk of nephrotoxicity.
209 Vancomycin also
causes, though rarely, thrombocytopenia and neutropenia.
56,58, 73
ANTIFUNGALS
Numerous antifungals are available. Toxicity related to the use of anti-
fungals is variable and is based generally on their mechanism of action.
AMPHOTERICIN B
Amphotericin B is a potent antifungal derived from Streptomyces
nodosus. Amphotericin B is generally fungistatic against fungi that con-
tain sterols in their cell membrane.
Table 56–1 lists the pharmacologic
mechanism of amphotericin B, and
Table 56–2 lists its pharmacokinetic
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826 Part C The Clinical Basis of Medical Toxicology
properties. Development of lipid and colloidal formulations of amphot-
ericin B attenuate the adverse effects associated with amphotericin B.
104
In these preparations, the amphotericin B is complexed with either a
lipid or cholesteryl sulfate. On contact with a fungus, lipases are released
to free the complexed amphotericin B, resulting in focused cell death.
113
There are several case reports of amphotericin B overdose in infants
and children. Significant clinical findings include hypokalemia, increased
aspartate aminotransferase concentrations, and cardiac complications.
Dysrhythmias and cardiac arrest have occurred following doses of 5 to
15 mg/kg of amphotericin B.
36, 58, 137 Care should be used in the doses of
amphotericin B administered according to dosage form, as these are not
interchangeable. For example, intravenous therapy for fungal infections
includes a usual dose of 0.25 to 1 mg/kg/d of amphotericin B or 3 to
4 mg/kg/d of amphotericin B cholesteryl. The potential for significant
dosage errors and their sequelae is readily apparent in this comparison.
Adverse Effects Associated With Therapeutic Use Infusion of amphot-
ericin B results in fever, rigors, headache, nausea, vomiting, hypoten-
sion, tachycardia, and dyspnea.
161 Pretreatment with acetaminophen,
diphenhydramine, ibuprofen, and hydrocortisone is helpful in alleviat-
ing the febrile symptoms, as are slower rates of infusion and lower total
daily doses.
95, 247 Doses greater than 1 mg/kg/d and rapid administration
of drug in less than 1 hour are not recommended. Infusion concentra-
tions of amphotericin B greater than 0.1 mg/mL can result in localized
phlebitis. Slower infusion rates, hot packs, and frequent line flushing
with dextrose in water may help to alleviate symptoms.
Eighty percent of patients exposed to amphotericin B will sustain
some degree of renal insufficiency (Chap. 27).
47 Initial distal renal
tubule damage causes renal artery vasoconstriction ultimately resulting
in azotemia.
83 Studies in animals show depressed renal blood flow and
glomerular filtration rate, and increased renal vascular resistance. It is
unclear why this occurs, but at this time, renal nerves, angiotensin II,
nitric oxide, and tubuloglomerular feedback are excluded.
210, 216 The
toxic effects associated with amphotericin B may also be caused by
the deoxycholate vehicle.
267 After large total doses of amphotericin B,
residual decreases in glomerular filtration rate may occur even after
discontinuation of therapy. This is hypothesized to be the result of
nephrocalcinosis. Potassium and magnesium wasting, proteinuria,
decreased renal concentrating ability, renal tubular acidosis, and
hematuria also occur (Chap. 16).
15, 161 Strategies to reduce renal toxic-
ity after amphotericin B include intravenous saline or magnesium and
potassium supplementation.
34, 84, 112 Liposomal formulations of amphot-
ericin B resulted in fewer patients with breakthrough fungal infections,
infusion-related fever, rigors, or nephrotoxicity.
258 However, chest pain
is uniquely reported after use of the liposomal agent.
130
Other adverse effects reported after treatment with amphotericin B include
normochromic, normocytic anemia secondary to decreased erythropoietin
release;159 respiratory insufficiency with infiltrates; and, rarely, dysrhythmias,
tinnitus, thrombocytopenia, peripheral neuropathy, and leukopenia.
153,159, 161
Exchange transfusion may be useful in neonates and infants and
should be considered after large intravenous exposures. In adults,
extracorporeal elimination is not expected to be useful because of the
low water solubility and high blood-protein binding of the drug.
AZOLE ANTIFUNGALS: TRIAZOLE AND IMIDAZOLES
Fluconazole
N
N
N
N
N
NCCC
OH
F
F
Common triazole antifungals include fluconazole, itraconazole, and
voriconazole. Common imidazoles include clotrimazole, econazole,
ketoconazole, and miconazole. Triazole antifungals are active to
treat an array of fungal pathogens, whereas imidazoles are used
almost exclusively in the treatment of superficial mycoses and vaginal
candidiasis. Severe toxicity is not expected in the overdose setting.
Hepatotoxicity, thrombocytopenia, and neutropenia are uncommon.
31
Rare case reports implicate voriconazole in the development of toxic
epidermal necrolysis.
117 The majority of toxic effects noted after the
use of these drugs result from their drug interactions. Fluconazole,
itraconazole, ketoconazole, and miconazole competitively inhibit
CYP3A4, the enzyme system responsible for the metabolism of many
drugs.
Table 56–5 lists other organ system manifestations associated
with antifungal agents and other antimicrobials.
ANTIPARASITICS
Antiparasitics such as thiabendazole, mebendazole, albendazole, dieth-
ylcarbazine, ivermectin, metrifonate, niclosamide, oxamniquine, piper-
azine, priziquantel, and pyrantel pamoate generally have a low level of
toxicity in the overdose setting. Common symptoms after therapeutic
use are gastrointestinal in nature and include abdominal pain, nausea,
vomiting, and diarrhea. A single case of ivermectin-associated hepatic
failure is reported 1 month after a single dose.
252
ANTIVIRAL
Acyclovir is well tolerated in therapeutic doses and overdoses,
although data are limited. In 105 dogs ingesting 40 to 2195 mg/kg,
gastrointestinal symptoms were most common with one dog develop-
ing mild creatinine increases.
200 Depressed mental status and nephro-
toxicity are also reported after therapeutic use in humans.
32
ANTIMICROBIALS SPECIFIC TO THE TREATMENT
OF HUMAN IMMUNODEFICIENCY VIRUS
AND RELATED INFECTIONS
The evaluation and management of patients infected with the human
immunodeficiency virus (HIV) and associated acquired immune defi-
ciency syndrome (AIDS) is ever evolving at a rapid and progressive pace.
Medications used to manage this disorder have dramatically increased
life expectancy as new, more powerful antiviral agents and drug combi-
nations become available. Drug therapy for HIV commonly consists of
a combination of drugs from different classes (nucleoside reverse tran-
scriptase inhibitor [NRTI], nonnucleoside reverse transcriptase inhibi-
tor [NNRTI], and protease inhibitor) in order to take advantage of the
unique mechanism that each drug offers in inhibiting viral replication
and minimizing drug resistance. Resistance patterns to the typical drugs
used in attenuating viral replication and proliferation are a substantial
issue and will continue to be addressed with yet more evolution in man-
agement in the foreseeable future. This section focuses on overdoses and
major toxic effects from HIV-directed antiviral therapy, as well as from
drugs that are specifically used in the management of opportunistic
infections. 20 Table 56–6 lists the common antibiotic agents used to treat
HIV-related opportunistic infections, and
Table 56–7 lists common
adverse drug effects and overdose effects, if known, for antimicrobials
that are specific in their use for HIV-related infections.
SPECIFIC ANTIRETROVIRAL CLASSES
Nucleoside Analog Reverse Transcriptase Inhibitors The nucleoside
analog reverse transcriptase inhibitors inhibit the reverse transcription
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Chapter 56 Antimicrobials, Antifungals, and Antivirals
TABLE 56–6. Antimicrobials Used to Treat
Common Opportunistic Infections
20
Antimicrobial Opportunistic Infection
Albendazole Microsporidiosis
Amphotericin B Aspergillosis
Coccidioidomycosis
Cryptococcosis
Histoplasmosis
Leishmaniasis
Paracoccidioidomycosis
Penicilliosis
Antimony (pentavalent) Leishmaniasis
Atovaquone Pneumocystis jiroveci
Azithromycin Mycobacterium avium complex
Clarithromycin Mycobacterium avium complex
Caspofungin Aspergillosis
Clindamycin Pneumocystis jiroveci
Toxoplasma gondii
Dapsone Pneumocystis jiroveci
Ethambutol Mycobacterium avium complex
Fluconazole Coccidioidomycosis
Histoplasmosis
Flucytosine Cryptococcosis
Foscarnet Cytomegalovirus
Fumagillin Microsporidiosis
Ganciclovir Cytomegalovirus
Itraconazole Histoplasmosis
Leucovorin Pneumocystis jiroveci
Toxoplasma gondii
Nitazoxanide Cryptosporidiosis
Microsporidiosis
Paromomycin Cryptosporidiosis
Pentamidine Pneumocystis jiroveci
Primaquine Pneumocystis jiroveci
Pyrimethamine Toxoplasma gondii
Rifabutin Mycobacterium avium complex
Sulfadiazine Toxoplasma gondii
Trimethoprin- Pneumocystis jiroveci
sulfamethoxazole Toxoplasma gondii
Isosporiasis
Trimetrexate Pneumocystis jiroveci
Valganciclovir Cytomegalovirus
Voriconazole Aspergillosis
of viral RNA into proviral DNA. Currently available drugs include
abacavir (ABC), emtricitabine (FTC), didanosine (ddI), lamivudine
(3TC), stavudine (d4T), tenofovir (TDF), zidovudine (AZT, ZDV), and
zalcitabine (ddC).
Acute Overdose Effects. Many intentional overdoses of reverse tran-
scriptase inhibitors occur without major toxicologic effect. The most
serious adverse effect anticipated after acute overdose of an NRTI is
TABLE 56–5. Consequential Organ System
Manifestations Associated With Antimicrobials
Antimicrobial System Signs, Symptoms, Laboratory
Antibacterials
Bacitracin Immune Hypersensitivity reactions
Clindamycin Immune Hypersensitivity reactions
Gastrointestinal Nausea, vomiting, diarrhea
Nervous Dizziness, headache, vertigo
Colistimethate Renal Decreased function, acute
(colistin sulfate) tubular necrosis
Nervous Peripheral paresthesias, confusion,
coma, seizures, neuromuscular
blockade
Lincomycin Gastrointestinal Nausea, vomiting, diarrhea
Immune Hypersensitivity reactions
Metronidazole Neurologic Peripheral neuropathy, seizures
Gastrointestinal Nausea, vomiting
Other Disulfiram reactions
Nitrofurazone Immune Hypersensitivity reactions
Other Ointment contains polyethylene
glycols (renal dysfunction)
Nitrofurantoin Gastrointestinal Nausea, vomiting, diarrhea
Hepatic Jaundice
Immune Rash, acute and chronic pulmonary
hypersensitivity
Neurologic Peripheral neuropathy
Novobiocin Immune Rash
Gastrointestinal Nausea, vomiting, diarrhea
Hematologic Pancytopenia, hemolytic anemia
Polymyxin B sulfate Neurologic Muscle weakness, seizures
Renal Azotemia, proteinuria
Selenium sulfide Cutaneous Contact dermatitis, alopecia (rare)
Silver sulfadiazine Cutaneous Contact dermatitis
Hematologic Anemia, aplastic anemia
Spectinomycin Immune Rash (rare)
Antifungals
Benzoic acid Gastrointestinal Nausea, vomiting, diarrhea
Carbol-fuchsin Gastrointestinal Nausea, vomiting, diarrhea
solution (phenol/
resorcinol/ fuchsin)
Gentian violet Gastrointestinal Nausea, vomiting, diarrhea
Immune Rash (rare)
Griseofulvin Renal Proteinuria, nephrosis
Hepatic Increased enzymes
Gastrointestinal Nausea, vomiting, diarrhea
Immune Granulocytopenia
Other Disulfiram reactions, increased
porphyrins
Nystatin Gastrointestinal Nausea, vomiting, diarrhea
Salicylic acid Gastrointestinal Higher concentrations are caustic
and dermal
Undecylenic acid and Gastrointestinal Nausea, vomiting, diarrhea
undecylenate salt
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828 Part C The Clinical Basis of Medical Toxicology
the development of a lactic acidemia, which appears to be more com-
mon in women.
52, 81, 162 Following incorporation of the nucleoside ana-
log into mitochondrial DNA by RNA polymerase, DNA polymerase
γ is inhibited. This results in decreased production of mitochondrial
DNA electron transport proteins, which ultimately inhibits oxidative
phosphorylation (Chap. 12). Organ system toxicity follows in addition
to the development of acidemia. The reported mortality in patients
with NRTI-associated metabolic acidosis associated with elevated
lactate is 33% to 57%.
81 Resolution of symptoms in survivors is
1 to 24 weeks. Patients with NRTI-associated acidemia may recover
more quickly after the use of cofactors such as thiamine, riboflavin,
-carnitine, vitamin C, and antioxidants.
38,71 The indications for the
use of these drugs are unclear at this time; however, because of the
relative lack of toxicity, they may be considered.
Chronic Effects. Development of acidemia is more commonly associ-
ated with therapeutic use of reverse transcriptase inhibitors than with
acute overdose. The mechanism is likely identical to that described
above. Other common adverse effects are somewhat agent specific
and include hematologic toxicity after zidovidine,
71, 98 pancreatitis with
didanosine, 145 hypersensitivity after abacavir,
70 and sensory peripheral
neuropathy after zalcitabine, stavudine, and didanosine.
171
Nonnucleoside Reverse Transcriptase Inhibitors NNRTI bind directly
to reverse transcriptase enzymes enabling allosteric inhibition of
enzymatic function.
243 Delavirdine (Rescriptor), etravirine (Intelence),
efavirenz (Sustiva), and nevirapine (Viramune) comprise the currently
available agents.
There are no substantial acute overdose data on these drugs, although
they generally appear to be safe in overdose. Treatment should include
TABLE 56–7. Antimicrobials Used in the Treatment of HIV-Related Infections
20
Antimicrobial Overdose Effects Common Adverse Drug Effects
Albendazole No reported cases Increased AST/ALT, nausea, vomiting, and diarrhea. Hematologic,
rare—encephalopathy, renal failure, rash
Antimony (pentavalent) Acute tubular necrosis Acute tubular necrosis. Multiorgan system failure
Atovaquone No clinical relevant effects in reported Rashes, anemia, leukopenia, increased AST/ALT
cases
55
Caspofungin No reported cases Phlebitis, headache, hypokalemia, increased AST/ALT, fever
Flucytosine No reported cases Bone marrow suppression, hepatotoxicity, nausea, vomiting, diarrhea, and rash
Foscarnet No reported cases Azotemia, hypocalcemia and renal failure (common); anemia, leukopenia,
thrombocytopenia, fever, headache, seizures, genital and oral ulcers,
fixed-drug eruptions, nausea, vomiting, diarrhea, headaches, seizures,
coma, diabetes insipidus, hypophosphatemia, hypokalemia, and
hypomagnesemia
Fumagillin No reported cases Neutropenia and thrombocytopenia
Ganciclovir No clinical relevant effects in Leukopenia, worsening of renal function; can also cause nausea, vomiting,
reported cases
138 diarrhea, increased AST/ALT, anemia, thrombocytopenia, headache, dizziness,
confusion, seizures
Nitazoxzanide No reported cases Hypotension, headache, abdominal pain, nausea, vomiting; may cause
green-yellow urine discoloration
Pentamidine 40 times dosing error in a 17-month-old Hypoglycemia (early) followed by hyperglycemia, azotemia; can cause
child resulted in cardiac arrest
259 hypotension, torsades de pointes, phlebitis, rash, Stevens-Johnson syndrome,
hypocalcemia, hypokalemia, anorexia, nausea, vomiting, metallic taste,
leukopenia, and thrombocytopenia
Primaquine No reported cases Granulocytopenia, hemolytic anemia, methemoglobinemia, leukocytosis;
hypertension
Pyrimethamine No reported cases Agranulocytosis, aplastic anemia, thrombocytopenia, and leukopenia
Rifabutin High doses (>1 g daily): arthralgia/ Nausea, vomiting, diarrhea; can cause hepatotoxicity, neutropenia,
arthritis thrombocytopenia, and hypersensitivity reactions
Sulfadiazine Acute renal failure and hypoglycemia 63 Rash, Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema
multiforme; headaches, depression, hallucinations, ataxia, tremor, crystalluria,
hematuria, proteinuria, and nephrolithiasis
Trimetrexate No reported cases; treat similar to Myelosuppression, nausea, vomiting, histaminergic reactions
methotrexate (Chap. 53)
Valganciclovir No reported cases; expect to be similar to Anemia, neutropenia, thrombocytopenia; nausea, vomiting, headache,
ganciclovir peripheral neuropathy
AST/ALT, serum alanine aminotransferase or serum aspartate aminotransferase.
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Chapter 56 Antimicrobials, Antifungals, and Antivirals
supportive care until more information is available. The NNRTIs are
also limited in toxicity after chronic use. Nevirapine and delavirdine
use commonly results in hypersensitivity reactions such as rash.
69
Efavirenz is reported to result in dizziness and dysphoria. Otherwise,
toxicity can result from the ability of these drugs to either inhibit or
enhance CYP isozymes in the metabolism of other drugs.
Protease Inhibitors Protease inhibitors inhibit the vital enzyme
(proteinase), which is required for viral replication.
85 Currently
available drugs include ataznavir (Reyatax), darunavir (Prezista),
fosamprenavor (Lexiva), indinavir (Crixivan), lopinavir (Kaletra),
nelfinavir (Viracept), ritonavir (Norvir), saquinavir mesylate (Invirase),
and tipranavir (Aptivus).
Data after protease inhibitor overdose are limited. A review of
data submitted to the manufacturer of indinavir found that of
79 reports, the complaints were nausea, vomiting, abdominal pain,
and nephrolithiasis. Protease inhibitors as a class commonly result in
gastrointestinal symptoms and rash.
85 A unique finding is an altered fat
distribution pattern that, over time, results in lymphodystrophy central
obesity, “buffalo hump,” breast enlargement, cushingoid appearance,
and peripheral wasting.
85
Entry/Fusion Inhibitors This class of drugs interferes with the binding
or entry of the HIV viron into the cell.
26 No acute overdose data are
available for this class, but after chronic use, hypersensitivity, hepato-
toxicity, and infusion reactions seem to be of greatest concern.
18, 174, 180
The currently available agents include enfuvirtide (Fuzeon) and mara-
viroc (Selzentry).
Integrace Inhibitor This class of drugs prevents the activity of the
enzyme in HIV to function normally. This enzyme is responsible for
the incorporation of the virus into DNA. The currently available agent
is raltegravir (Isentress). No information is currently available regard-
ing its toxicity.
SUMMARY
Adverse effects attributable to antimicrobials are largely related to
chronic administration, although rarely acute toxicity does occur.
Acute toxic effects of antimicrobials are more common following
intravenous administration, drug interactions, or iatrogenic overdose.
Vigilance on the part of the healthcare provider will prevent the major-
ity of acute toxic manifestations following antimicrobial use.
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