D: ANTIMICROBIALS

HISTORY AND EPIDEMIOLOGY

The introduction of penicillin in the 1940s revolutionized the care of patients with infectious diseases. Antimicrobials, including all categories of antibacterials, antifungals, and antivirals, significantly improve the clinical care and ­outcome of infected patients. Since early in their introduction, the development of antimicrobial-resistant strains of these pathogens has driven an increase in the number of antimicrobials necessary. This, in turn, continues to increase the overall potential for toxicity after use. Fortunately, with most antimicrobials, toxicity due to acute overdose is limited and chronic therapeutic doses are safe.

Most adverse drug events related to antimicrobials occur as a result of iatrogenic complications rather than intentional overdose. The diverse origins of these complications include dosing errors, route administration errors, allergic reactions, adverse drug events, and drug–drug-related interactions. Prevention, in the form of process improvements and information regarding populations at risk for adverse drug events, is continually required to minimize these untoward events. Dosing errors are prominent, particularly in neonates and infants, and those patients with compromised kidney or liver function necessitating care and constant diligence on the part of health care professionals.

Antimicrobials are more commonly associated with allergic reactions than are other pharmaceuticals. The reason is hypothesized to be either a result of their high frequency of use, repeated intermittent prescriptions, or environmental contamination. A complete allergy history is essential to minimize these adverse drug reactions in patients being considered for antimicrobial therapy.

Many adverse drug reactions attributed to antimicrobials are difficult to predict even when given patient and population specific parameters. In some cases, an excipient is found responsible for the adverse event, as is seen after the use of procaine penicillin G (Chap. 46). Antimicrobials are involved in many common and severe drug–drug interactions, ­primarily through the inhibition of cytochrome and other metabolic enzymes. Patients considered for antimicrobial therapy should be carefully assessed for the use of prescription and nonprescription therapies that are known to be pharmacokinetically or pharmacodynamically affected by the chosen antimicrobial.

PHARMACOLOGY AND TOXICOLOGY

Antimicrobial pharmacology is aimed at the destruction of microorganisms through the inhibition of cell cycle reproduction or the altering of a critical function within a microorganism. Table 54–1 lists antimicrobials and their associated mechanisms of activity, toxicologic effects, and related toxicologic mechanisms. Often the mechanisms for toxicologic effects following acute overdose differ from their therapeutic mechanisms.

ANTIBACTERIALS

Aminoglycosides

Aminoglycosides that are in current use in the United States include amikacin, gentamicin, kanamycin, neomycin, paromomycin, streptomycin, and tobramycin. Aminoglycosides are available in parenteral, topical, and ophthalmic forms. Overdoses, almost exclusively the result of dosing errors, are rarely life threatening, and most patients can be safely managed with minimal intervention.^28,122 Adverse drug reactions, seen after aminoglycoside use, are generally class based, although subtle differences exist in the potency with which the adverse drug reactions occur (Table 54–2).

Large intravenous doses of aminoglycosides are both sufficiently safe and effective for use in single daily doses.⁵ Rarely, acute aminoglycoside overdose results in nephrotoxicity, ototoxicity, or vestibular toxicity.^117,143 In one reported case, postmortem analysis confirmed a complete loss of hair cells in the inner and outer cochlear (Chap. 25).

Aminoglycosides exacerbate concomitant neuromuscular blockade, particularly at times corresponding to high peak serum aminoglycoside concentrations (Chap. 66).¹⁷³ This is caused by inhibiting presynaptic calcium channels, thereby inhibiting the release of acetylcholine from presynaptic nerve terminals. Patients at risk for enhanced neuromuscular blockade include those with abnormal neuromuscular junction function, such as occurs with myasthenia gravis or botulism.

Adverse Drug Reactions Associated With Therapeutic Use

Adverse drug reactions, including nephrotoxicity and ototoxicity, correlate most closely with elevated trough serum concentrations than with elevated peak ­concentrations.^109,152 Less common adverse drug reactions associated with chronic use include electrolyte abnormalities, allergic reactions, hepatotoxicity, anemia, granulocytopenia, thrombocytopenia, eosinophilia, ­retinal toxicity, reproductive dysfunction, tetany, and psychosis.^{113,128,214,228} When aminoglycosides are administered at high doses or during once-daily dosing, sepsislike chills and malaise occur, which are likely due to excipients delivered during the infusion.⁵¹

Nephrotoxicity

The mechanism of nephrotoxicity and ototoxicity is incompletely understood, but involves the formation of reactive oxygen species in the presence of iron. Both the inhibition of mitochondrial respiration resulting in lipid peroxidation and the stimulation of glutamate activated N-methyl-D-aspartate (NMDA) receptors are hypothesized to play a role.^98,238 The incidence of nephrotoxicity with aminoglycoside therapy is estimated at 10% to 25%.¹¹⁸ Although the aminoglycosides are almost completely excreted prior to biotransformation in the kidney, a small fraction of filtered aminoglycoside is transported by absorptive endocytosis across the apical membrane of proximal tubular cells where it becomes sequestered within lysosomes. As toxicity progresses, lysosomes rupture allowing the sequestered aminoglycoside to binds to and destroy phospholipids contained on brush border membranes in the proximal renal tubule.⁹

In addition to tubular toxicity renal injury occurs through effects on the glomerulus and vascular system. Acute kidney injury does not generally occurs before 7 to 10 days of standard-dose therapy.¹⁴¹ Because the injury occurs days prior to elevations in serum creatinine concentration, a delay in diagnosis is common.²⁰¹ Laboratory abnormalities include granular casts, proteinuria, elevated urinary sodium, and increased fractional excretion of sodium. Usually acute kidney injury (AKI) is reversible. Gentamicin and tobramycin have a higher total incidence of nephrotoxicity compared with netilmicin and amikacin.¹¹⁸ Risk factors for the development of nephrotoxicity­ include increasing age, chronic kidney disease (CKD), female sex, previous aminoglycoside therapy, liver dysfunction, large total dose, long duration of therapy, frequent doses, high trough concentrations, the presence of other nephrotoxic xenobiotics, and shock.^9,156 Because the uptake of aminoglycosides into organs is saturable, once-daily high-dose regimens are less problematic than several lesser doses given in a single day.

Ototoxicity

Ototoxicity occurs after acute or prolonged exposure to aminoglycosides (Chap 25).²⁰³ Both cochlear and vestibular dysfunction occur and injury is thought to result from prolonged contact time with sensory hair cells after bioaccumulation in the endolymph and perilymph spaces.⁴ 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 54–2 details the relative characteristic toxicity of various aminoglycosides.

Full-tone audiometric testing first shows high-frequency hearing loss, which subsequently progress in select cases. Given the inability of cochlear hair cells to regenerate, all hearing loss that develops is permanent. After early diagnosis of vestibular dysfunction, select patients improve after ­discontinuation of the xenobiotic. Simultaneous administration of other ototoxic xenobiotics enhances the ototoxicity of aminoglycosides (Chap. 25).

Withdrawal of the offending xenobiotic is indicated in patients with either nephrotoxicity or ototoxicity caused by an aminoglycoside antibiotic (Chap. 27). Supportive care is the mainstay of therapy. N-Acetylcysteine reduced the rate of ototoxicity in patients with end-stage renal failure when given concurrently with aminoglycosides.¹²⁴ Experimental treatments in ­animal models include the use of deferoxamine and glutathione in an attempt to chelate and/or detoxify a reactive intermediate.^167,217 The antibiotic ticarcillin forms a renally eliminated complex with aminoglycosides; however, this is of limited value because in most instances the serum concentration of the aminoglycoside has decreased before any therapeutic measures can be used.⁷⁵

Penicillins

Penicillin is derived from the fungus Penicillium and many semisynthetic derivatives have found clinical utility. Penicillins, as a class, contain a 6-aminopenicillanic acid nucleus, composed of a β-lactam ring fused to a 5-member thiazolidine ring. Classically available penicillins include penicillin G, penicillin V, and the antistaphylococcal penicillins (nafcillin, oxacillin, and dicloxacillin). Penicillins developed to enhance the spectrum of antibiotic efficacy, particularly against gram-negative bacilli, include the second-generation penicillins (ampicillin, and amoxicillin), third-generation penicillins (ticarcillin), and fourth-generation penicillins (piperacillin). Table 54–1 lists the pharmacologic mechanism of penicillins.

Acute oral overdoses of the various penicillins are usually not life ­threatening.²²² The most frequent complaints following acute overdose are nausea, vomiting, and diarrhea.

Seizures can occur in persons given large intravenous or cerebral intraventricular doses of penicillins.^114,125,150 More than 50 million units administered intravenously in less than 8 hours is generally required to produce seizures in adults.²⁰⁶ Penicillin-induced seizures are mediated through binding to the ­picrotoxin-binding site on the neuronal chloride channel near the γ-aminobutyric acid (GABA)–binding site (Chap. 13).⁹⁶ Binding of the penicillin to this site produces an allosteric change in the receptor and prevents GABA from binding, resulting in a relative loss of inhibitory tone.²⁶ Seizures appear to be related to structure of the beta-lactam ring because penicillin analogs (such as imipenem) also cause seizures, presumably through a similar mechanism.⁵⁷

The treatment of patients who develop penicillin-induced seizures should emphasize benzodiazepines followed by other GABA agonists, if necessary. Patients who receive an intraventricular overdose, where greater than 10,000 units or equivalent is administered, often require cerebrospinal fluid exchange or perfusion to attenuate seizure activity (Special ­Considerations: SC7).^46,125,154 There are rare reports of hyperkalemia resulting in electrocardiographic abnormalities after the rapid intravenous infusion of potassium penicillin G to patients with CKD and other reports of amoxicillin overdose resulting in frank hematuria and AKI.^36,88

Adverse Drug Reactions Associated With Therapeutic Use

Penicillins are associated with a myriad of adverse drug reactions after therapeutic use, the most common of which are allergic in nature.²² Penicillins are commonly implicated in immune-related reactions such as bone marrow suppression, cholestasis, hemolysis, interstitial nephritis, and vasculitis.^8,86,104,216 Rare reactions include pemphigus after penicillin use and corneal damage after the use of methicillin.^19,248

Acute Allergy

Penicillins are the pharmaceuticals most commonly implicated in the development of acute anaphylactic reactions. Anaphylactic reactions are severe, life-threatening, immunoglobulin E (IgE)–mediated immune reactions involving multiple organ systems that typically occur immediately after exposure. Table 54–3 lists the classifications of anaphylactic reactions. Anaphylaxis to penicillin occurs only after IgE antibody formation, which requires prior exposure, although that exposure could be obscure (eg, through consumption of meat from animals fed antibiotics). Life-threatening clinical manifestations include angioedema, tongue and airway edema, bronchospasm, bronchorrhea, dysrhythmias, cardiovascular collapse, and cardiac arrest.⁷⁶ 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 an immune response, including leukotrienes, C₄ and D₄, histamine, eosinophilic chemotactic factor, and other vasoactive substances, such as bradykinin, kallikrein, prostaglandin D₂, and platelet-activating factor (Fig. 54–1).

The incidence of penicillin hypersensitivity occurs in 5% of patients, with 1% of penicillin reactions manifesting as anaphylaxis. The risk for a fatal hypersensitivity after penicillin administration is 2 in 100,000 (0.002%) patient exposures.²³⁶ 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. Specific therapy for anaphylaxis is epinephrine 0.01 mg/kg in children (0.3-0.5 mg in adults) given as 1:1,000 (1 mg/mL) dilution intramuscularly (IM) every 5 to 15 minutes.^155,212 Epinephrine bronchodilates and increases cardiac output through β-adrenergic receptor stimulation. In addition, β-adrenergic receptor stimulation results in decreased peripheral vascular tone and decreased mast cell release of mediators. Oxygen, intravenous use of epinephrine (1 mcg/min of 1:100,000 or 1:250,000), intravenous crystalloid, and inhaled β₂-adrenergic agonists are warranted in severe cases, as are corticosteroids.²⁴⁹ Refractory cases of hypotension may respond to glucagon and methylene blue administration (Antidotes in Depth: A20 and A43). H₁-receptor antagonists and H₂-receptor antagonists are useful as second-line therapeutic agents, and can be used to attenuate minor effects such as urticaria or pruritus.

Amoxicillin-Clavulanic Acid and Drug-Induced Liver Injury (DILI)

The predominant distribution of penicillin-induced hepatotoxicity is cholestatic hepatitis, which typically occurs 1 to 8 weeks after initiation of therapy.⁷ The incidence of DILI is estimated at 1 per 2,300 prescriptions and is the most common cause of DILI in the United States and Europe.²⁵ The mechanism of hepatotoxicity is not clear, but it is hypothesized to be immunoallergic and 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 findings typically resolve after the discontinuation of therapy. However, prolonged hepatitis, ductopenia (vanishing bile duct syndrome), and pancreatitis rarely occur.^53,182 Behavioral disturbances with disorientation, agitation, and visual hallucinations temporally related to use are also reported.¹⁶

Hoigne Syndrome and Jarisch–Herxheimer Reaction

The most common adverse drug reactions occurring after administration of large intramuscular or intravenous doses of procaine penicillin G are the Hoigne syndrome and the Jarisch–Herxheimer reaction.^111,148 The Hoigne syndrome is characterized by extreme apprehension and fear, illusions, or hallucinations; both visual and auditory, tachycardia, systolic hypertension, and, occasionally, seizures that begin within minutes of injection.²³⁵ These effects occur in the absence of signs or symptoms of anaphylaxis. Procaine is implicated as the etiology because of the similarity to events that occur after the administration of other local anesthetics known as the so-called caine reaction.^197,208,231 Hoigne syndrome is 6 times more common in men than in women.²¹¹ The reason for this increased prevalence is unclear, but autosomal dominance and influences of prostaglandin and thromboxane A₂ activity occur in this population.¹²

The Jarisch–Herxheimer reaction is a self-limited reaction that develops within a few hours of antibiotic therapy for the treatment of spirochetal ­diseases such as syphilis or Lyme disease, leptospirosis, and in Q fever. Myalgias, chills, headache, rash, and fever spontaneously resolve within 18 to 24 hours, even with continued antibiotic therapy.²⁰⁷ The pathogenesis of this reaction is likely either endotoxin induced from the lysed spirochete or cytokine elevation.¹⁷⁷ Antiinflammatory medications and immune modulators such as anti-TNF can be considered, but the optimal treatment is still unclear.

Cephalosporins

Cephalosporins are semisynthetic derivatives of cephalosporin C produced by the fungus Acremonium, previously called Cephalosporium. Cephalosporins have a ring structure similar to that of penicillins and are generally divided into first, second, third, fourth, and fifth generations based on their antimicrobial spectrum. First-generation cephalosporins include cefadroxil, cefazolin, and cephalexin. Second-generation cephalosporins include cefaclor, cefditoren, cefotetan, cefoxitin, cefprozil, and cefuroxime. Third-generation cephalosporins include cefdinir, ceftazidime, cefixime, ceftibuten, cefotaxime, ceftriaxone, and cefpodoxime. The fourth-generation cephalosporin is cefepime, and the fifth-generation cephalosporins are ceftaroline and ceftolozane.

Effects occurring after acute overdose of cephalosporins resemble those occurring with penicillins. Some cephalosporins also have epileptogenic potential similar to penicillin.²³⁹ Case reports demonstrate seizures after inadvertent intraventricular administration.^39,131,251 Management of cephalosporin overdose is similar to that of penicillin overdose. Table 54–1 lists the pharmacologic mechanism of cephalosporins.

Adverse Drug Reactions Associated With Therapeutic Use

Cephalosporins rarely cause an immune-mediated acute hemolytic crisis.⁷³ Cefaclor is the cephalosporin most commonly reported to cause systemic immune complex hypersensitivity or serum sickness, although this can occur with other cephalosporins.^119,142 Also like penicillins, first-generation cephalosporins are associated with chronic toxicity, including interstitial nephritis and hepatitis.²⁴⁵ Cefepime is reported to cause reversible coma and seizures.^1,215

Cross-Hypersensitivity

The cephalosporins contain a 6-member dihydrothiazine ring instead of the 5-member thiazolidine penicillin ring. The extent of cross-reactivity between penicillins and cephalosporins in an individual patient is largely determined by the type of penicillin allergic response experienced by the patient and the structural similarity of the beta lactam side determinants.¹⁸⁹ The incidence of anaphylaxis to cephalosporins is between 0.0001% and 0.1%, with a threefold increase in patients with previous penicillin allergy.¹²⁰ The overall cross-reactivity rate is approximately 1% between penicillin and a first- or second-generation cephalosporin. Cross-reactivity between penicillin and third-, fourth-, or fifth-generation cephalosporins is likely to be negligible because of a dissimilar antigenic side chain.⁴⁷ 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 first- or second-generation cephalosporins in penicillin- or cephalosporin-allergic patients; however, if a risk-to-benefit analysis demonstrates a clear benefit to the patient without equivalent alternatives, the cephalosporin should be given.

N-Methylthiotetrazole Side-Chain Effects

Cefazolin and cefotetan are the only available cephalosporins containing an N-methylthiotetrazole (nMTT) side chain. As these cephalosporins undergo metabolism, they release free nMTT, which (Fig. 54–2) inhibits the enzyme aldehyde dehydrogenase.¹⁵¹ In conjunction with ethanol consumption, use of these medications can cause a disulfiramlike reaction (Chaps. 76 and 78).⁴³

The nMTT side chain is also associated with hypoprothrombinemia, although a causal relationship is controversial.⁹⁵ It is thought that nMTT depletes vitamin K–dependent clotting factors by inhibition of vitamin K epoxide reductase.¹⁶⁹ In a study of children one month to one year of age who were maintained on a prolonged antibiotic regimen, a significant degree of vitamin K depletion was found.²¹ Treatment of patients suspected of hypoprothrombinemia caused by these cephalosporins consists of clotting factor replacement, if bleeding is evident, and vitamin K₁ in doses required to reactivate vitamin K cofactors (Chap. 58 and Antidotes in Depth: A17).

Other β-Lactam Antimicrobials

Included in this group are monobactams such as aztreonam and carbapenems such as doripenem, ertapenem, imipenem/cilastatin, and meropenem. Table 54–1 lists the pharmacologic mechanism of these xenobiotics.

Effects occurring after acute overdose and the management of other β-lactam antimicrobials resemble those occurring after penicillin exposure. Imipenem has epileptogenic potential in both overdose and therapeutic dosing and at a higher risk than other carbapenems.⁴⁸

Adverse Drug Reactions Associated With Therapeutic Use

The risk factors for developing imipenem-related seizures include central nervous system disease, prior seizure disorder, and abnormal kidney function.¹⁷⁵ The mechanism for seizures is GABA antagonism (similar to the penicillins) in conjunction with enhanced activity of excitatory amino acids.^65,220

Cross-Hypersensitivity

Aztreonam is a monobactam that does not contain the antigenic components required for cross-allergy with penicillins, and generalized cross-allergenicity is not expected.²⁰⁰ However, aztreonam cross-reacts in vitro with ceftriaxone, thought to be the result of the similarity in their side-chain structure.¹⁷⁴ Skin test–manifested cross-allergenicity has also been noted between imipenem and penicillin, although the clinical incidence of adverse reactions is yet to be determined.¹⁹⁹

Trimethoprim–Sulfamethoxazole

Trimethoprim and sulfamethoxazole work in tandem as antibacterials effectively preventing tetrahydrofolic acid synthesis in bacterial cells. ­Significant toxicity after acute overdose is not expected; however, a myriad of adverse drug reactions occur after chronic therapeutic use. Hyperkalemia can result as a result of the ability of trimethoprim to competitively inhibit sodium channels in the distal nephron, causing impairment in renal potassium excretion. Clinically significant hyperkalemia is reported in patients concurrently on other xenobiotics that increase potassium and among those with CKD.^71,166 Other effects commonly reported after use of trimethoprim/sulfamethoxazole combinations include cutaneous allergic reactions, hematologic disorders, methemoglobinemia, hypoglycemia, rhabdomyolysis, neonatal kernicterus, and psychosis.^157,226

Trimethoprim also inhibits the renal tubular secretion of creatinine, resulting in an increase in serum creatinine measurement.⁶⁶ This effect is thought to be dose related and increases in creatinine ranges from 13% to 35%. The rise in creatinine is independent of glomerular filtration rate and resolves on drug discontinuation.

Chloramphenicol

Chloramphenicol was originally derived from Streptomyces venezuelae and is now synthetically produced. Antimicrobial activity is demonstrated against many gram-positive and gram-negative aerobes and anaerobes.

Chloramphenicol inhibits protein synthesis in rapidly proliferating cells. Metabolic acidosis occurs as a result of the inhibition of mitochondrial enzymes, oxidative phosphorylation, and mitochondrial biogenesis.²⁴⁶ Table 54–1 lists the pharmacologic mechanism of chloramphenicol.

Acute overdose of chloramphenicol commonly causes nausea and ­vomiting. Infrequently, sudden cardiovascular collapse can occur 5 to 12 hours after acute overdoses. Cardiovascular compromise is more frequent in patients with serum concentrations higher than 50 mcg/mL.^85,159,224 Because tissue concentration measurements are not readily available, all poisoned patients should be closely observed for at least 12 hours after exposure. Orogastric lavage should be used after recent ingestions when the patient has not vomited, and oral or nasogastric activated charcoal 1 g/kg should also be given.

Extracorporeal means of eliminating chloramphenicol are not usually required because of its rapid metabolism. However, hemodialysis, charcoal hemoperfusion, and exchange transfusion in neonates all decrease serum chloramphenicol concentrations. These extracorporeal procedures should be employed in patients presenting early after a life-threatening history of ingestion, particularly if they have severe hepatic or renal dysfunction.^{83,153,213,218} Surviving patients should be closely monitored for signs of bone marrow suppression, which is dose dependent.

Adverse Drug Reactions 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.”¹⁵⁹ Children with this syndrome exhibit vomiting, anorexia, respiratory distress, abdominal distension, green stools, lethargy, cyanosis, ashen color, metabolic acidosis, hypotension, and cardiovascular collapse.

Approximately 90% of systemic 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 chloramphenicol in the urine.^92,244

There are 2 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.^107,170,205 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 occurs through inhibition of protein synthesis in the mitochondria of marrow cell lines.¹⁶¹ This type causes the development of aplastic anemia, which is not dose related, generally occurs in susceptible patients within 5 months of treatment and has an approximately 50% mortality rate (Chap. 20).^72,253 The dihydro 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.¹¹⁵

Other adverse drug reactions associated with chloramphenicol include peripheral neuropathy, neurologic abnormalities (eg, confusion, delirium), optic neuritis, nonlymphocytic leukemia, and contact dermatitis.^{61,126,136,179,210}

Fluoroquinolones

The fluoroquinolones are a structurally similar, synthetically derived group of antimicrobials that have diverse antimicrobial activities. They include ciprofloxacin, gatifloxacin (ophthalmic only), gemifloxacin, levofloxacin, moxifloxacin, norfloxacin, and ofloxacin. 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 54–1 lists the pharmacologic mechanism of fluoroquinolones.

Rarely, acute overdose of a fluoroquinolone results in AKI or seizures.¹²⁹ The mechanism of AKI after fluoroquinolone exposure is controversial. In animals, ciprofloxacin and norfloxacin are nephrotoxic, especially in the setting of neutral or alkaline urine.^63,202 In humans, AKI is reported after both acute and chronic exposure to fluoroquinolones. A hypersensitivity reaction is postulated to explain pathologic changes consistent with interstitial nephritis.^105,185 Treatment includes discontinuation of the fluoroquinolone and supportive care. Improvement in kidney function usually occurs within several days.

Seizures are reported with ciprofloxacin and likely result from the inhibition of GABA or from elevation of neuronal glutamate.^2,58 Other authors 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 magnesium at the excitatory NMDA-gated ion channel (Chap. 13).⁶⁵ Treatment is supportive, using benzodiazepines and, if necessary, barbiturates to increase inhibitory tone.

Adverse Drug Reactions Associated With Therapeutic Use

Several fluoroquinolones are substrates and/or inhibitors of CYP enzymes. This can result in xenobiotic interactions, which are especially important with xenobiotics that have a narrow therapeutic index.

Serious adverse drug reactions related to fluoroquinolone use consist of central nervous system toxicity (as discussed), cardiovascular toxicity, hepatotoxicity, and notable musculoskeletal toxicity.

Fluoroquinolones prolong the QT interval, and are reported to result in torsade de pointes.¹⁷² Prolongation is due to the ability of fluoroquinolones to block the rapid component of the delayed rectifier potassium current (I_Kr). Treatment of patients presenting with QT interval prolongation includes immediate discontinuation of the offending drug and supportive care (Chap. 15).

Fluoroquinolones also rarely result in potentially fatal hepatotoxicity.¹³⁸ This adverse effect was most notable with trovafloxacin, which was withdrawn from the US market.

Fluoroquinolones should be used with caution in children and pregnant women because of their potential adverse drug reactions on developing cartilage and bone.²³ There is a higher incidence of bone, joint, tendon, and muscle abnormalities in children treated with a fluoroquinolone versus alternative antibiotic therapy, which persists months after the completion of drug therapy. When followed long-term, however, it was found that these abnormalities are generally reversible. Women who received quinolones during pregnancy had larger babies and more cesarean deliveries because of fetal distress than did controls.¹⁸

Fluoroquinolones are implicated as a cause of tendon rupture, most commonly the Achilles, which is reported to occur for months to years after the start of treatment as well as after the discontinuation of therapy. An FDA review concluded that because of these risks, these drugs should be reserved for when there is no alternative available.¹⁸¹ Risk factors include age 60 years or older, concomitant corticosteroid use, AKI or CKD, female sex, and lack of obesity.^132,247 The fluoroquinolone should be discontinued in patients, particularly athletes, who complain of symptoms consistent with painful and swollen tendons.

Macrolides and Ketolides

The macrolide antimicrobials include various forms of erythromycin (base, ethylsuccinate, gluceptate, lactobionate, stearate), azithromycin, clarithromycin, and fidaxomicin. Ketolides are similar in pharmacology to macrolides; telithromycin is the only available xenobiotic at this time. Table 54–1 lists the pharmacologic mechanism of macrolides and ketolides.

Acute oral overdoses of macrolide antimicrobials are not life threatening, and symptoms, which are generally confined to the gastrointestinal tract, include nausea, vomiting, and diarrhea. Intravenous overdoses can cause dysrhythmias.²²⁷

Intravenous and oral therapeutic use of macrolides cause QT interval prolongation and dysrhythmias.⁵⁵ The QT interval prolongation seen occurs as a result of blockade of delayed rectifier potassium currents I_Kr (Chaps. 15 and 57).¹⁸⁶ Macrolide-associated oxidative stress to mitochondrial cells subsequently inhibited hERG potassium conductance in rat cardiomyocytes exposed to various macrolides.¹⁹⁵ The relative risk in a large meta-analysis for sudden cardiac death was 2.42, and ventricular tachydysrhythmia was 2.52, in patients who took macrolides versus those who did not. In children, intravenous overdoses of azithromycin resulted in similar findings.²²⁷

Although there are no acute overdose data regarding ketolide antimicrobials, effects are expected to be similar to macrolide antimicrobials. Therapeutic use of telithromycin is reported to result in QT interval prolongation, hepatotoxicity, toxic epidermal necrolysis, and anaphylaxis.^37,40

Adverse Events Associated With Interactions With Xenobiotics

Erythromycin is the prototypical macrolide and, as such, has received the most attention with respect to potential and documented xenobiotic interactions. Clarithromycin, erythromycin, and troleandomycin are all potent inhibitors of CYP3A4; azithromycin does not inhibit this enzyme.⁶⁴ Erythromycin inhibits CYP enzymes after metabolism to a nitroso intermediate, which then forms an inactive complex with the iron (II) of cytochrome P450. The appendix to Chap. 11 lists substrates for CYP3A4. Clinically significant interactions occur with erythromycin and warfarin, carbamazepine, or cyclosporine.^44,100,178 Inhibition of cisapride metabolism results in increased concentrations of the parent xenobiotic, which is capable of causing prolongation of the QT interval and causing torsade de pointes.³³ Cases of carbamazepine toxicity are documented when combined with the use of erythromycin.¹⁰⁰ Erythromycin also inhibits CYP1A2, producing clinically significant interactions with clozapine, theophylline, and warfarin.¹⁸⁸

Macrolides interact with the absorption and renal excretion of xenobiotics that are substrates for P-glycoprotein, and they also interfere with the normal gut flora responsible for metabolism. This is hypothesized to be part of the underlying mechanism of cases of macrolide-induced digoxin toxicity, for example (Chap. 62).¹⁶⁸

End-Organ Effects

The most common toxic effect of macrolides after chronic use is hepatitis, which is hypothesized to be immune mediated.⁴⁹ Erythromycin estolate is the macrolide most frequently implicated in causing cholestatic hepatitis.^91,112

Large doses (>4 g/day) of macrolides are associated with high-frequency sensorineural hearing loss that typically resolves following discontinuation of therapy.^41,135 Renal impairment is noted to be a risk ­factor.^193,221 Other, rare toxic effects associated with macrolides include cataracts after clarithromycin use in animals and acute pancreatitis in humans.^78,234 Allergy is rare and reported at a rate of 0.4% to 3%.⁶⁷ Telithromycin contains a carbamate side chain that is hypothesized to 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.¹²¹

Clindamycin is a lincosamide with structure and clinical effects similar to macrolides’. Clindamycin phosphate is commonly used topically while clindamycin hydrochloride is available intravenously and clindamycin palmitate hydrochloride is available for oral use. Data regarding acute overdose are limited. Neuromuscular blockade is reported after intravenous dosing errors.³ The most consequential toxicity seen after therapeutic doses is esophageal ulcers, diarrhea, and Clostridium difficile–mediated enterocolitis.¹⁸⁶

Sulfonamides

Sulfonamides antagonize para-aminobenzoic acid or para-aminobenzyl glutamic acid, which are required for the biosynthesis of folic acid. Table 54–1 lists the pharmacologic mechanism of sulfonamides. Acute oral overdoses of sulfonamides are usually not life threatening, and symptoms are generally confined to nausea, although allergy and methemoglobinemia occur rarely.⁸² Treatment is similar to acute oral penicillin overdoses.

Adverse Drug Reactions Associated With Therapeutic Use

The most common adverse drug reactions associated with sulfonamide therapy are nausea and cutaneous hypersensitivity reactions.⁸⁹ Hypersensitivity reactions are caused by 2 mechanisms. The first is an IgE-mediated response to the heterocyclic ring at the sulfonamide-N1 position. The more common allergic response occurs 7 to 14 days after initiation of therapy and requires an unsubstituted amine group at the N4 position of the sulfonamide. 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 experienced by the patient.¹³⁴ This is caused by a reduction in the mechanisms available for detoxification of free radical formation, as cysteine and glutathione concentrations are low in these patients.²⁴¹

Methemoglobinemia and hemolysis occur rarely.^70,162 The mechanism for adverse reactions is not entirely clear. However, when sulfamethoxazole is exposed to ultraviolet B radiation in vitro, free radicals are formed that can participate in the development of tissue peroxidation and hemolysis.²⁵³ This finding is of particular importance in treating patients with glucose-6-phosphate dehydrogenase deficiency associated with decrease in reducing capabilities.⁶

The sulfonamides are associated with many chronic adverse drug reactions. Bone marrow suppression is rare, but the incidence is increased in patients with folic acid or vitamin B₁₂ deficiency, and in children, pregnant women, alcoholics, dialysis patients, and immunocompromised patients, as well as in patients who are receiving other folate antagonists. Other adverse drug reactions include hypersensitivity pneumonitis, Stevens–Johnson syndrome, toxic epidermal necrolysis, stomatitis, aseptic meningitis, hepatotoxicity, renal injury, and central nervous system toxicity.²⁹

Tetracyclines

Tetracyclines are produced by Streptomyces. Currently available tetracyclines include demeclocycline, doxycycline, minocycline, and tetracycline. Table 54–1 lists the pharmacologic mechanism of tetracyclines. Significant toxicity after acute overdose of tetracyclines is unlikely. Gastrointestinal effects consisting of nausea, vomiting, and epigastric pain are reported.⁴²

Adverse Drug Reactions Associated With Therapeutic Use

Tetracycline should not be used in children during the first 6 to 8 years of life or by pregnant women after the 12th week of gestation because of the risk for secondary tooth discoloration in children or fetuses.¹⁹⁶ Tooth discoloration can be effectively mitigated using topical application of carbamide peroxide whitening treatments.²²⁹ Other effects associated with tetracyclines include nephrotoxicity, hepatotoxicity, skin hyperpigmentation in sun-exposed areas, and hypersensitivity reactions.^{49,94,110,223} More severe hypersensitivity reactions, vertigo, xenobiotic-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.^145,204,209 Demeclocycline rarely causes nephrogenic diabetes insipidus (Chaps. 12 and 27).⁵⁰ Degraded tetracycline is reported to result in reversible Fanconi syndrome.⁸⁴ Epi-anhydrotetracycline or anhydrotetracycline were likely the causative toxins.

Vancomycin

Vancomycin is obtained from cultures of Nocardia orientalis and is a ­tricyclic glycopeptide. Vancomycin is biologically active against numerous gram-positive organisms. Table 54–1 lists the pharmacologic mechanism of vancomycin.

Acute oral overdoses of vancomycin rarely cause significant toxicity and most cases can be treated with supportive care alone. After large iatrogenic, rapidly infused intravenous overdoses, AKI can occur in patients with preexisting kidney disease because of sustained high serum concentrations. In these patients, multiple doses of activated charcoal and hemodialysis are effective in enhancing clearance.^127,233

Adverse Drug Reactions Associated with Therapeutic Use

Rapid infusions of intravenous vancomycin and the subsequent development of the “red man syndrome” occurs through an anaphylactoid (non–IgE-mediated) mechanism.⁸⁷ Symptoms include chest pain, dyspnea, pruritus, urticaria, flushing, and angioedema.¹⁹⁰ Spontaneous resolution occurs typically within 15 minutes. Other symptoms attributable to “red man syndrome” include hypotension, cardiovascular collapse, and seizures.^13,164

The incidence of red man syndrome is approximately 14% when 1 g is given over 10 minutes, and falls dramatically to only 3.4% when given over one hour.^164,171 A trial in 11 healthy persons studied the relationship between intradermal skin hypersensitivity and the development of red man syndrome. Each of the 11 study participants underwent skin testing that was followed one week later by an intravenous dose of vancomycin 15 mg/kg over 60 minutes. Following intravenous vancomycin, all participants developed dermal flare responses and erythema, and 10 of 11 participants developed pruritus within 20 to 45 minutes. After the infusion was terminated, symptoms resolved within 60 minutes.¹⁷⁶

The signs and symptoms of this syndrome are related to the rise and fall of histamine concentrations.^137,194 Tachyphylaxis occurs in patients given multiple doses of vancomycin.^99,240 Animal models demonstrated a direct myocardial depressant and vasodilatory effect of vancomycin.⁶² More serious reactions result when vancomycin is given via intravenous bolus, further supporting a rate-related anaphylactoid mechanism.²⁰ In rare cases, oral administration of vancomycin can also result in red man syndrome.¹⁷

Treatment includes increasing the dilution of vancomycin and slowing intravenous administration. Antihistamines are useful as pretreatment, especially prior to the first dose.¹⁸⁰ A placebo-controlled trial in adult patients given 1 g of vancomycin over one hour noted a 47% incidence of reaction without diphenhydramine and a 0% incidence with diphenhydramine.²⁴⁰

Chronic use of vancomycin results in reversible nephrotoxicity, particularly in patients with prolonged excessive steady-state serum concentrations.^10,184 Concomitant administration of aminoglycoside antimicrobials increases the risk of nephrotoxicity.¹⁹¹ Vancomycin also causes, though rarely, thrombocytopenia and neutropenia.^59,69

ANTIFUNGALS

Numerous antifungals are available. Toxicity related to the use of antifungals 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 contain sterols in their cell membrane. Table 54–1 lists the pharmacologic mechanism of amphotericin B. Development of lipid and colloidal formulations of amphotericin B attenuate the adverse drug reactions associated with amphotericin B.⁹⁷ 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.¹⁰²

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.^35,60,123 Care should be used in the doses of amphotericin B administered according to specific formulation design, as these are not interchangeable. For example, intravenous therapy for fungal infections includes a usual dose of 0.25 to 1 mg/kg/day of amphotericin B or 3 to 4 mg/kg/day of amphotericin B cholesteryl. The potential for significant dosage errors and their sequelae is readily apparent in this comparison.

Adverse Drug Reactions Associated With Therapeutic Use

Infusion of amphotericin B results in fever, rigors, headache, nausea, vomiting, hypotension, tachycardia, and dyspnea.¹⁴⁶ Slower rates of infusion and lower total daily doses mitigate symptoms of early infusion–related reactions as does pretreatment with diphenhydramine. In addition, acetaminophen, ibuprofen, and hydrocortisone are helpful in alleviating febrile effects.^90,232 Doses greater than 1 mg/kg/day and rapid administration in less than one hour are not recommended. Infusion concentrations 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 is recommended help to alleviate symptoms.

Eighty percent of patients exposed to amphotericin B will sustain some degree of kidney dysfunction (Chap. 27).⁴⁵ Initial distal renal tubule damage causes renal artery vasoconstriction, ultimately resulting in azotemia.⁷⁹ 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, and nitric oxide are excluded as etiologies.^192,198 The toxic effects associated with amphotericin B are likely caused by the deoxycholate vehicle, which accounts for differences seen with the liposomal form.^133,252 After large total doses of amphotericin B, residual decreases in glomerular filtration rate 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 can also occur (Chaps. 12 and 27).^14,146 Strategies to reduce renal toxicity after amphotericin B include intravenous saline or magnesium and potassium supplementation.^32,80,101 Liposomal formulations of amphotericin B resulted in fewer patients with breakthrough fungal infections, infusion-related fever, rigors, or nephrotoxicity.²⁴² However, chest pain is uniquely reported after use of the liposomal preparation.¹¹⁶

Other adverse drug reactions reported after treatment with amphotericin B include normochromic, normocytic anemia secondary to decreased erythropoietin release; respiratory insufficiency with infiltrates; and, rarely, dysrhythmias, tinnitus, thrombocytopenia, peripheral neuropathy, and leukopenia.^139,144,146

Exchange transfusion should be used in neonates and infants after large intravenous overdoses. There is a single case of the successful use of plasmapheresis concurrent with hemodialysis for evolving AKI in a 60-year-old female who had inadvertent administration of amphotericin B deoxycholate 250 mg (4.3 mg/kg) over 2 hours instead of a liposomal product.²⁴³

Azole Antifungals: Triazole and Imidazoles

Triazole antifungals include fluconazole, isavuconazonium, itraconazole, posaconazole, terconazole, and voriconazole. Common imidazoles include butoconazole, clotrimazole, econazole, ketoconazole, miconazole, and tioconazole. Triazole antifungals 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.³⁰ Rare case reports implicate voriconazole in the development of toxic epidermal necrolysis.¹⁰⁶ Most of the toxic effects noted after the use of these xenobiotics result from their xenobiotic interactions. Fluconazole, itraconazole, ketoconazole, and miconazole competitively inhibit CYP3A4, the isoenzyme system responsible for the metabolism of many xenobiotics. Table 54–4 lists other organ system manifestations associated with antifungal agents and other antimicrobials.

ANTIPARASITICS

Antiparasitics such as mebendazole, albendazole, ivermectin, praziquantel, and pyrantel pamoate generally have limited toxicity in overdoses, although significant toxicity can be found after the use of antimalarials for the treatment of malaria (Chap. 55). 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 has been reported one month after a single dose.²³⁷

ANTIVIRALS

Acyclovir, famciclovir, and valacyclovir are generally well tolerated in therapeutic doses and overdoses. Neurotoxicity and, less commonly, AKI are reported after therapeutic use in humans, and similar findings are expected after overdose.³¹ The most common neurotoxic complaints include lethargy, confusion, and ataxia.¹⁰⁸ Acute kidney injury occurs as the result of precipitation of acyclovir crystals within the renal tubules with resultant obstructive effects.²³⁰ In 105 dogs ingesting 40 to 2,195 mg/kg, gastrointestinal symptoms were most common, with one dog developing mild creatinine increases.¹⁸³ A single case report describes a patient with AKI with crystalluria after ingestion of 30 g of valacyclovir.¹⁸⁷

ANTIMICROBIALS SPECIFIC TO THE TREATMENT OF HIV AND RELATED INFECTIONS

The evaluation and management of patients infected with HIV/AIDS continues to evolve. Medications used to manage this disorder have increased life expectancy as new, more powerful antivirals and xenobiotic combinations become available. Therapeutic for HIV commonly consists of a combination of xenobiotics from different classes. The current recommendations include highly active antiretroviral therapy (HAART), which involves the use of 2 nucleoside reverse transcriptase inhibitors (NRTI) along with a third antiretroviral drug. Options include a integrase strand transfer inhibitor (INSTI), a non-nucleoside reverse transcriptase inhibitor (NNRTI), a protease inhibitor (PI) with a pharmacokinetic enhancer (cobicistat or ritonavir), or a C-C chemokine receptor type 5 (CCR5) antagonist.¹⁰³ The unique mechanisms that each xenobiotic offers aids in inhibiting viral replication and in minimizing xenobiotic resistance. Drug and dosage errors, particularly in infants, are of significant concern and have resulted in iatrogenic overdose.^34,56,140 These drugs also have success in the antiviral treatment of hepatitis C infection.⁵⁴ Second-generation protease inhibitors have revolutionized the care of these patients in that they can be used in combinations that exclude the need for interferon and ribavirin while achieving higher sustained virologic responses.²⁵⁰ This section focuses on overdoses and major toxic effects from HIV-directed antiviral therapy, as well as from xenobiotics that are specifically used in the management of opportunistic infections. A comprehensive review of these medications and end-organ toxicities is available.¹⁴⁹ Several drug interactions are also possible because of these xenobiotics being substrates for both inducers and inhibitors of ­several CYP enzymes and P-glycoprotein–associated metabolic systems.²¹⁹ Table 54–5 lists the common antimicrobials used to treat HIV-related opportunistic infections, and their common adverse effects.

Specific Antiretroviral Classes

Nucleoside Analog Reverse Transcriptase Inhibitors

The nucleoside analog reverse transcriptase inhibitors inhibit the reverse transcription of viral RNA into its subsequent DNA through the use of nucleoside analogs. Currently available xenobiotics include abacavir, didanosine (ddI), emtricitabine, lamivudine, stavudine, and zidovudine.

Acute Overdose Effects

Many intentional overdoses of reverse transcriptase inhibitors occur without major toxicologic effect. The most serious adverse effect anticipated after acute overdose of an NRTI is the development of a metabolic acidosis with elevated lactate concentration, which appears to be more common in women.^52,77,147 After the incorporation of the nucleoside analog into mitochondrial DNA by viral RNA reverse transcriptase enzymes, the faulty DNA results in impaired polymerase gamma activity. This results in decreased production of mitochondrial DNA electron transport proteins, which ultimately inhibits oxidative phosphorylation (Chap. 11). 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%.⁷⁷ Resolution of symptoms in survivors occurs within 1 to 24 weeks. Patients with NRTI-associated acidemia are reported to recover more quickly after the use of cofactors such as thiamine, riboflavin, L-carnitine, vitamin C, and antioxidants.³⁸ The indications for the use of these xenobiotics are unclear at this time; however, because of the relative lack of toxicity, administration is reasonable.

Chronic Effects

Development of acidemia is more commonly associated with therapeutic use of reverse transcriptase inhibitors than with acute overdose. The mechanism is likely identical to that described above. Other drug-specific adverse drug reactions include hematologic toxicity after zidovudine, pancreatitis with didanosine, hypersensitivity after abacavir, and sensory peripheral neuropathy, after stavudine and didanosine.^{67,68,93,130,158}

Nonnucleoside Reverse Transcriptase Inhibitors

The nonnucleoside reverse transcriptase inhibitors bind directly to reverse transcriptase enzymes enabling allosteric inhibition of enzymatic function.²²⁵ Delavirdine, efavirenz, etravirine, nevirapine, and rilpivirine comprise the currently available xenobiotics.

There is a paucity of acute overdose data on these xenobiotics, although they generally appear to have limited toxicity. An adult male with a reported ingestion of 6 g of nevirapine had a sustained laboratory elevation in gamma-glutamyl transferase, but no other reported effects.⁷⁴ An infant received a 40 times therapeutic dose of nevirapine with mild neutropenia and metabolic acidosis with elevated lactate concentration.³⁴ Finally, a 12-year-old child reported an ingestion of 3 g of efavirenz resulting in throat burning, visual impairment, peripheral nervous system abnormalities, and nightmares.¹⁶³ Treatment is entirely supportive until more information is available. The nonnucleoside reverse transcriptase inhibitors are also limited in toxicity after chronic use. Use of nevirapine and delavirdine ­commonly results in hypersensitivity reactions such as rash. Efavirenz is reported to result in dizziness and dysphoria. Otherwise, toxicity can result from the ability of these xenobiotics to either inhibit or enhance CYP isozymes in the metabolism of other xenobiotics.

Protease Inhibitors

Protease inhibitors inhibit the vital enzyme (protease), which is required for viral replication.⁸¹ Currently available xenobiotics include atazanavir, darunavir, fosamprenavir, indinavir, nelfinavir, ritonavir, saquinavir, and tipranavir.

Data after protease inhibitor overdose are limited. A literature review found diarrhea and hyperlipidemia to be common findings after therapeutic use. Less common were hepatitis, rash, hyperbilirubinemia, paresthesias, and nephrolithiasis.²⁷ Drug interactions can occur due to almost uniform inhibition of CYP3A-enzymes, and effects on P-glycoprotein along with some having effects and/or substrates for other CYP isoenzymes.²¹⁹ 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.⁸¹

Fusion Inhibitors

This class of xenobiotics interferes with the binding or entry of the HIV virion into the cell.²⁴ No acute overdose data are available for this class, but after chronic use, hypersensitivity, gastrointestinal complaints, hepatotoxicity, and infusion reactions seem to be of greatest concern.^15,160,165 The currently available drug is enfuvirtide.

Cellular Chemokine Receptor (Ccr5) Antagonist

These drugs bind to chemokine coreceptors found on CD4 cells, which then ultimately prevents the entry of the HIV virion into the cell. The currently available drug is maraviroc. There is no overdose and adverse events reported; however, maraviroc has a boxed warning due to another CCR5 inhibitor, which was halted in development because of substantial hepatotoxicity.¹⁶⁵

Integrase Inhibitor

This class of xenobiotics 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 xenobiotics are dolutegravir, elvitegravir, and raltegravir. No information is currently available regarding its toxicity after acute overdose. It appears that these xenobiotics are well tolerated at therapeutic doses.

SUMMARY

• Adverse drug reactions attributable to antimicrobials are largely related to chronic administration, although, rarely, acute severe toxic effects occur after large exposures.

• Acute toxic effects of antimicrobials are far more common following intravenous administration, xenobiotic interactions, or after iatrogenic overdose.

• Vigilance on the part of the health care professionals will prevent the majority of acute toxic manifestations following antimicrobial use.

REFERENCES

INTRODUCTION

The malaria parasite has caused untold grief throughout human history. The name originated from Italian mal aria (bad air) because the ancient Romans believed the disease was caused by the decay in marshes and swamps and was carried by the malodorous “foul” air emanating from these areas.⁸ In the 1880s, both the Plasmodium protozoa and its mosquito vector were ­identified.⁸ Today, nearly half of the world’s population lives in areas where malaria is endemic. Despite markedly decreased mortality rates over the last 7 years, malaria remains a significant cause of morbidity and mortality worldwide. In 2015, there were 212 million estimated malaria cases, leading to 429,000 deaths.¹¹⁹ Most of these deaths were from Plasmodium falciparum infections of young children and primigravid pregnant women in Africa.¹⁵ Included among those at risk of becoming infected are 50 million travelers from industrialized countries who visit the developing countries each year. Despite using prophylactic medications, an estimated 30,000 of these travelers will acquire malaria.⁹⁶

MALARIA OVERVIEW

Malaria is an infection of protozoan parasites in the Plasmodium genus with a unique life cycle involving the Anopheles mosquito as vector. Today malaria is primarily endemic in tropical and subtropical areas worldwide. It was once endemic in temperate areas, including Western Europe and the United States, but economic development and improvements in ­public health hastened its retreat.⁴⁵ Malaria was fully eradicated from the United States between 1947 and 1951 owing in large part to the powerful insecticidal effects of dichloro diphenyl trichloroethane (DDT).⁴⁵ The emergence of DDT-resistant Anopheles mosquitoes and chloroquine-resistant Plasmodium spp has impeded eradication in other parts of the world.⁴⁵

Malaria has a unique life cycle (Fig. 55–1) beginning with inoculation of sporozoites from an infected female Anopheles saliva. The sporozoites travel to the liver, where they invade the host’s hepatocytes and undergo asexual division (asexual exoerythrocytic cycle), ultimately causing rupture of the infected hepatocyte (tissue schizont) and release of thousands of merozoites into the bloodstream.⁵ The tissue phase is complete at this point with the exception of Plasmodium vivax and Plasmodium ovale, which can remain dormant in liver cells (hypnozoites), causing recurrent infections years later. The erythrocytic cycle begins when merozoites penetrate erythrocytes (trophozoites), undergoing additional cycles of asexual division (erythrocytic schizont), leading to cell rupture and the release of a new wave of merozoites to infect additional erythrocytes. This erythrocytic cycle is responsible for the clinical manifestations of malaria. Some erythrocytic merozoites differentiate into sexual forms (macrogametocytes {female} and microgametocytes {male}). Ingestion of both sexual forms by the female Anopheles during a blood meal allows fertilization and zygote formation in the mosquito midgut epithelium (sporogenic cycle), ultimately leading to rupture of an oocyst and release of sporozoites that migrate to the salivary glands, awaiting injection into another victim.¹¹⁵

Six Plasmodium spp cause malaria in humans (Table 55–1). The majority of cases worldwide are caused by P. falciparum and P. vivax, with P. falciparum responsible for the overwhelming majority of deaths.⁷⁶ Traditional teaching highlights the synchronization of blood parasite cycles causing a somewhat predictable fever periodicity, described as tertian or quartan fever, depending on the causative organism. These classic periodic fevers are rarely observed in Western countries because symptomatic cases are diagnosed earlier than in the past.⁵ The routine use of antipyretics probably also contributes to atypical presentations.

Unlike the other forms of human malaria, Plasmodium knowlesi is a true zoonosis, the natural host being macaques (Macaca spp) and related monkey species. Natural transmission of a nonhuman Plasmodium spp to humans was thought to be rare, but increasing numbers of P. knowlesi malarial infections are reported in and around Malaysia, Indonesia, and Southeast Asia, causing scientists to include this parasite as a potential human pathogen.⁵⁴

ANTIMALARIAL HISTORY

It is somewhat ironic that despite sophisticated drug development ­methods and advanced technologies of the 21st century, the most widely used old treatments (quinine and its derivatives) and the best new regimens (artemisinins) have both been used for centuries as ancient herbal remedies derived from plants.

The bark of the cinchona tree, the first effective remedy for malaria, was introduced to Europeans more than 350 years ago.¹¹⁴ The toxicity of its active ingredient, quinine, was noted from the inception of its use. Pharmaceutical advances occurred, funded largely by the US military during World War II, yielding 4-aminoquinolines, 8-aminoquinolines, and novel antifolates. To combat emerging strains of drug-resistant P. falciparum that developed ­during the Vietnam conflict, alternate quinine derivatives (amino alcohols) were developed.^106,114 Other drugs used to treat malaria include the folate inhibitors, selected antibiotics, the sulfonamide sulfadoxine, the tetracyclines, and the macrolides (Chap. 54).

With the introduction of each new drug, resistance developed, particularly in Oceania, Southeast Asia, and Africa.^106,114 In some instances, quinine is again the first-line therapy for malaria.¹¹⁸ In the past 2 decades, the search for active xenobiotics has returned to a natural product, the Chinese herb qinghaosu. The active metabolite, of which is dihydroartemisinin, is common to all the endoperoxides. These drugs are primarily used as part of an artemisinin-based combination therapy (ACT), which is recommended by the World Health Organization (WHO) as the preferred treatment of malaria in drug-resistant areas.^8,119 With increased leisure travel, a greater number of North Americans are taking prophylactic medications with potential toxicity.

This chapter highlights the toxicity of the most commonly used antimalarials using the structural and mechanistic classification outlined in Table 55–2.

AMINO ALCOHOLS

Antimalarial Mechanism

Unlike humans, who eliminate heme through the use of heme oxygenase ­ultimately producing the bile pigment biliverdin, Plasmodium spp convert heme to the nontoxic relatively inert compound hemozoin. Amino alcohols and 4-aminoquinolines concentrate in parasite food vacuoles, where they inhibit the ability of the parasite to detoxify hemozoin, leading to accumulation of toxic heme by-products and parasite death.^89,115 In resistant parasites, these antimalarials fail to concentrate in food vacuoles because of increased drug efflux. This resistance is thought to be conferred through amplification of a transmembrane pump. Interestingly, tricyclic antidepressants, phenothiazines, and calcium channel blockers reverse resistance in experimental models.⁸⁹

Quinine

The therapeutic benefits of the bark of the cinchona tree have been known for centuries. As early as 1633, cinchona bark was used for its antipyretic and analgesic effects,⁷⁵ and in the 1800s, it was used for the treatment of “rebellious palpitations.” Quinine, the primary alkaloid in cinchona bark, was the first effective treatment for malaria. Additionally, because of a reported curarelike action, quinine is infrequently used as a treatment for muscle cramps. Because of its extremely bitter taste similar to that of heroin, quinine is used as an adulterant in drugs of abuse. Small quantities of quinine can be also found in some tonic waters and bitter lemon drinks.

High doses of quinine and other cinchona alkaloids are oxytocic, potentially leading to abortion or premature labor in pregnant women. Because of this, quinine is occasionally used as an abortifacient (Chap. 19).⁷⁷ ­Chloroquine continues to be used as an abortifacient in some parts of the developing world.^11,90 Neither is safe as an abortifacient because of their narrow toxic-to-therapeutic ratio.

Pharmacokinetics and Toxicokinetics

See Table 55–3 for the pharmacokinetic properties of quinine. Quinine and quinidine are optical isomers and share similar pharmacologic effects as class IA antidysrhythmics and antimalarials. Both are extensively metabolized in the liver, kidneys, and muscles utilizing cytochrome P450 isoenzymes to a variety of hydroxylated metabolites. As such, quinine could alter the metabolism of other xenobiotics utilizing the same enzyme systems, especially CYP3A4, CYP2D6, and CYP1A2. Quinine is also highly protein bound, primarily to α-1-acid glycoproteins, providing an additional mode for potential drug–drug interactions. Quinidine’s volume of distribution varies from 0.5 L/kg in patients with congestive heart failure to 2 to 3 L/kg in healthy adults, to 3 to 5 L/kg in patients with cirrhosis.¹¹¹ The widely varied volume of distribution between healthy individuals, those with differing levels of parasitemia, and those with various comorbidities, is a shared property of all antimalarials. Quinine undergoes transplacental distribution and is secreted in breast milk.

Pathophysiology

Quinine overdose affects multiple organ systems through a number of ­different pathophysiologic mechanisms. Outcomes appear to be most closely related to the degree of cardiovascular dysfunction.⁴¹

Quinine and quinidine share anti- and prodysrhythmic effects primarily from an inhibiting effect on the cardiac sodium channels and potassium channels (Chaps. 15 and 57).⁴³ Blockade of the sodium channel in the inactivated state decreases inotropy, slows the rate of depolarization, slows conduction, and increases action potential duration. Inhibition of this rapid inward sodium current is increased at higher heart rates (called use-dependent blockade), leading to a rate-dependent widening of the QRS complex.^114,116

Inhibition of the potassium channels suppresses the repolarizing delayed rectifier potassium current, particularly the rapidly activating component,¹¹⁶ leading to prolongation of the QT interval. The resultant increase in the effective refractory period is also rate dependent, causing greater repolarization delay at slower heart rates and predisposing to torsade de pointes. As a result, syncope and sudden dysrhythmogenic death occur. This “quinidine syncope”—ventricular dysrhythmias or fibrillation—was identified more than half a century ago as a therapeutic complication.⁹⁹ An additional α-adrenergic antagonist effect contributes to the syncope and hypotension occurring in quinine toxicity. Quinidine possesses antimuscarinic activity in therapeutic dosing.⁵⁷

Inhibition of the adenosine triphosphate (ATP)–sensitive potassium channels of pancreatic β cells results in the release of insulin, similar to the action of sulfonylureas (Chap. 47).³² Patients at increased risk of quinine-induced hyperinsulinemia include those patients receiving high-dose intravenous (IV) quinine, intentional overdose, and patients with other metabolic stresses (eg, concurrent malaria, pregnancy, malnutrition, and ethanol consumption).^21,107

The mechanism of quinine-induced ototoxicity appears to be multifactorial. Microstructural lengthening of the outer hair cells of the cochlea and organ of Corti occurs.⁴⁸ Additionally, vasoconstriction and local prostaglandin inhibition within the organ of Corti contributes to decreased hearing.¹⁰⁶ Inhibition of the potassium channel also impairs hearing and produces vertigo because it is known that the homozygous absence of gene products that form part of some potassium channels (Jervell and Lange-Nielson syndrome) causes deafness and prolonged QT intervals (Chaps. 15 and 25).¹⁰⁵

Although older theories suggested that quinine caused retinal ischemia, the preponderance of evidence points to a direct toxic effect on the retina, and possibly the optic nerve fibers.³⁸ Quinine also antagonizes cholinergic neurotransmission in the inner synaptic layer.

Quinine has direct irritant effects on the gastrointestinal (GI) tract and stimulates the brain stem center responsible for nausea and emesis.¹¹⁴

Clinical Manifestations

Quinine overdose typically leads to GI complaints, tinnitus, and visual symptoms within hours, but the time course varies with the formulation ingested, coingestants, patient characteristics, and other case-specific details. ­Significant overdose is heralded by cardiovascular and central nervous system (CNS) toxicity. Death can occur within hours to days, usually from a combination of shock, ventricular dysrhythmias, respiratory arrest, or acute kidney injury (AKI).

Patients receiving even therapeutic doses often experience a syndrome known as “cinchonism,” which typically includes GI complaints, headache, vasodilation, tinnitus, and decreased hearing acuity.^75,114 Vertigo, syncope, dystonia, tachycardia, diarrhea, and abdominal pain are also described.^49,63

Quinine toxicity is correlated with total serum concentrations, but only the non–protein-bound portion is likely responsible for toxic effects. However, because free and total quinine concentrations vary widely from person to person,³⁷ a single quinine concentration does not always correlate with clinical toxicity. In general, serum concentrations greater than 5 mcg/mL cause cinchonism, greater than 10 mcg/mL visual impairment, greater than 15 mcg/mL cardiac dysrhythmias, and greater than 22 mcg/mL death.⁴ ­Similar concentrations in individuals who are severely ill with malaria do not necessarily result in as severe toxicity because an increase in plasma α₁-acid glycoprotein reduces the free fraction of quinine present.^97,101

The toxic-to-therapeutic ratio of quinine is very small. It is not surprising that patients taking therapeutic doses frequently develop toxicity because the recommended range of serum quinine concentrations for treatment of falciparum malaria is 5 to 15 mcg/mL, well above the concentration reported to cause cinchonism.

The average oral lethal dose of quinine is 8 g, although a dose as small as 1.5 g is reported to cause death.^39,49 Delirium, coma, and seizures are less common, usually occurring only after severe overdoses.¹⁸

Cardiovascular manifestations of quinine use are related to myocardial drug concentrations. They manifest on the electrocardiogram (ECG) as prolongation of the PR interval, prolongation of the QRS complex, prolongation of the QT interval, and ST depression with or without T wave inversion. Dysrhythmias and complete heart block are reported.¹⁶ Quinine toxicity can also result in significant hypotension.

Although not commonly reported, mild hyperinsulinemia and resultant hypoglycemia occur in cases of oral quinine overdose. Hypoglycemia with elevated serum insulin concentrations was documented after therapeutic dosing in case reports complicated by severe congestive heart failure and significant ethanol consumption. Hypoglycemia is also noted in healthy patients after overdose. Hypoglycemia is fairly common in patients with severe malaria treated with quinine, occurring in up to 10% of patients and 50% of pregnant women.¹⁰⁷

Eighth cranial nerve dysfunction results in tinnitus and deafness. The decreased acuity is not usually clinically apparent, although the patient recognizes tinnitus.⁹⁵ These findings usually resolve within 48 to 72 hours, and permanent hearing impairment is unlikely.

Ophthalmic presentations include blurred vision, visual field constriction, diplopia, altered color perception, mydriasis, photophobia, scotomata, and sometimes complete blindness.^18,44 The onset of blindness is invariably delayed and usually follows the onset of other manifestations by at least 6 hours. The pupillary dilation that occurs is usually nonreactive and correlates with the severity of visual loss. Funduscopic examination findings are occasionally normal but usually demonstrate extreme arteriolar constriction associated with retinal edema. Normal arteriolar caliber is commonly seen initially, but funduscopic manifestations such as vessel attenuation and disc pallor develop as clinical improvement occurs. Improvement in vision can occur rapidly but is usually slow, occurring over a period of months after a severe toxicity. Initially, improvement occurs centrally and is followed later by improvement in peripheral vision. The pupils occasionally remain dilated even after return to normal vision.³⁹ Patients with the greatest exposure frequently develop optic atrophy.

Hypokalemia is often described in the setting of quinine poisoning, although the mechanism is unclear. An intracellular shift of potassium rather than a true potassium deficit is the predominant theory behind the hypokalemia associated with chloroquine,^65,69 and the mechanism is assumed to be similar with quinine.

A number of immune-mediated hypersensitivity reactions are described. These are the result of antiquinine or antiquinine-hapten antibodies cross-reacting with a variety of membrane glycoproteins^19,56 dramatically increasing their binding affinity to cell-surface antigens by more than 10,000 times.⁴⁰ Asthma and dermatologic manifestations, such as urticaria, photosensitivity dermatitis, cutaneous vasculitis, lichen planus, and angioedema, also occur.¹⁰⁷

Hematologic manifestations of hypersensitivity include thrombocytopenia (Chap. 20), agranulocytosis, microangiopathic hemolytic anemia, and disseminated intravascular coagulation (DIC), which can lead to jaundice, hemoglobinuria, and AKI.^49,56 Quinine is recognized as a common cause of drug-induced thrombocytopenia and the most common cause of drug-induced thrombotic microangiopathy syndrome (characteristically microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury). Hemolysis also occurs in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. Severe multisystem hypersensitivity reactions can occur even after minute doses of quinine, such as those in tonic drinks.^40,60 This type of interaction has previously been termed “cocktail purpura.”^75,114

A hepatitis hypersensitivity reaction, acute respiratory distress syndrome (ARDS), and a sepsislike syndrome are also reported.

Diagnostic Testing

Urine thin-layer chromatography is sensitive enough to confirm the presence of quinine even after the ingestion of tonic water.¹²⁰ Quinine immunoassay techniques are also available. Quantitative serum testing is not rapidly or widely available.

Management

Patients frequently vomit spontaneously. Emetics should not be used in the absence of vomiting because seizures, dysrhythmias, and hypotension can occur rapidly. Orogastric lavage is not routinely recommended except for patients with recent, substantial (potentially life-threatening) ingestions with no spontaneous emesis. Activated charcoal effectively adsorbs quinine and additionally decreases serum concentrations by altering enteroenteric circulation⁶² but should only be administered in patients with a low risk of aspiration or protected airways.

Expectant treatment should be initiated, including oxygen, cardiac and hemodynamic monitoring, IV fluid resuscitation, and frequent ECG and blood glucose measurements. In general, patients should be monitored until vital signs normalize, mental status improves, and laboratory values stabilize. Variables including the amount ingested, patient comorbidities, and coingestions, highlight the importance of individualized care. Asymptomatic patients with suspected overdose should be monitored for 6 to 12 hours depending on variables as above, before medical clearance.

Extracorporeal membrane oxygenation was used in one case of severe quinidine poisoning with bradydysrhythmias and refractory hypotension to stabilize the cardiovascular system while a quinidine-activated charcoal bezoar was removed and the patient metabolized the remaining quinidine. A similar approach would be reasonable to consider for intractable quinine toxicity.

Cardiac

In patients with a conduction delay manifested by a QRS complex of more than 100 milliseconds (ms) we recommend treating with sodium bicarbonate alkalinization to achieve a serum pH of 7.45 to 7.50, as would be done in patients with cardiotoxicity associated with cyclic antidepressant overdoses (Antidotes in Depth: A5). Protein binding is increased in the setting of alkalemia, decreasing the cardiotoxic manifestations of quinine. Sodium bicarbonate therapy is successful in case reports^16,41,75 but has not been specifically studied. Since hypertonic sodium bicarbonate will worsen existing hypokalemia, potentially exacerbating the effect of potassium channel blockade.

Potassium supplementation for quinine-induced hypokalemia is controversial because experimental data from the 1960s suggest that hypokalemia is protective against cardiotoxicity and prolongs survival.^20,65,100 Because hypokalemia can also lead to lethal dysrhythmias, supplementation for significant hypokalemia (<3.0 mmol/L) is recommended as a reasonable intervention.

The QT interval should be carefully monitored for prolongation. If necessary, interventions for torsade de pointes, including magnesium administration, potassium supplementation, and overdrive pacing, should be initiated (Chap. 15 and Antidotes in Depth: A16).

Class IA, IC, or III antidysrhythmics and other xenobiotics with sodium channel or potassium channel blocking activity should not be used to treat quinine-overdosed patients because they would be expected to exacerbate quinine-induced conduction disturbances or dysrhythmias. The Class IB antidysrhythmics, such as lidocaine, have been used with reported success,⁴⁷ but no clinical trials have been performed (Chap. 57).

Hypotension refractory to IV crystalloid boluses should be treated with vasopressors. In controlled human studies, epinephrine infusions reverse quinidine’s antidysrhythmic drug effects and prolongation of the ventricular refractory period in a dose-dependent fashion.^22,74 Although not directly studied, direct-acting vasopressors such as epinephrine, norepinephrine, and phenylephrine are recommended. An intraaortic balloon pump was successfully used for the treatment of refractory hypotension in one case report.¹⁰⁰

Hypoglycemia

A low serum glucose concentration should be supported with an adequate infusion of dextrose. Serum potassium concentration and the QT interval should be monitored during correction and maintenance. Octreotide was successfully used to correct quinine-induced hyperinsulinemia in adult malaria victims.⁸⁶ In volunteers, quinine-induced hyperinsulinemia was suppressed within 15 minutes after a 100-mcg intramuscular dose of octreotide (Antidotes in Depth: A9).⁸⁵ Octreotide should be used for cases of refractory hypoglycemia in a fashion similar to that recommended in sulfonylurea toxicity, which is 50 mcg (1 mcg/kg in children) subcutaneously every 6 hours (Chap. 47).

Ophthalmic

Funduscopic examination, visual field examination, and color testing are appropriate bedside diagnostic studies. Electroretinography, electrooculography, visual-evoked potentials, and dark adaptation are helpful in assessing the injury but are not practical because they require equipment that is not portable or readily available in most clinical settings. There is no specific, effective treatment for quinine retinal toxicity.⁴⁶ Hyperbaric oxygen was used in 3 patients who recovered vision, but since its role in that recovery was not established, it cannot be routinely recommended at this time.¹²⁰

Enhanced Elimination

The effect of multiple-dose activated charcoal (MDAC) on quinine elimination was studied in an experimental human model and in symptomatic patients.⁸⁷ In these patients, MDAC decreased the half-life of quinine from approximately 8 hours to about 4.5 hours and increased clearance by 56%.⁹² Although numerous studies show that activated charcoal decreases quinine half-life,^13,62,87 evidence of clinical benefit is lacking. Nevertheless, because ophthalmic, CNS, and cardiovascular toxicity are related to serum concentration, it is prudent to reduce concentrations as quickly as practicable; thus, multiple-dose activated charcoal is recommended unless contraindications exist (Antidotes in Depth: A1).

There is conflicting evidence about a benefit of urinary acidification in enhancing clearance. But because of the increased potential for cardiotoxicity associated with acidification, this technique is never recommended.

Because quinine has a relatively large volume of distribution and is highly protein bound, hemoperfusion, hemodialysis, and exchange transfusion have only a limited effect on drug removal.^13,18,97,114 Although the blood compartment can be cleared with these techniques, total body clearance is only marginally altered. After rapid tissue distribution occurs, there is little impact on the total body burden because of the large volume of distribution and extensive protein binding; thus, extracorporeal methods of drug removal are not routinely recommended.

Mefloquine

Pharmacokinetics and Toxicodynamics

See Table 55–3 for the pharmacokinetic properties of mefloquine. Similar to its cousin quinine, mefloquine is hepatically metabolized by cytochrome P450 enzyme systems and excreted primarily in the bile and feces. Some hypothesize that the small, lipophilic structure combined with a long elimination half-life allows mefloquine to easily cross the blood–brain barrier, accumulate in the CNS, and interact with neuronal targets, leading to neurotoxic side effects.⁶⁷

Clinical Manifestations

Common side effects with prophylactic and therapeutic dosing include nausea, vomiting, and diarrhea. These side effects are noted particularly in the extremes of age and with high therapeutic dosing. Similar findings should be expected in acute overdose.^107,117

Mefloquine has a mild cardiodepressant effect, less than that of quinine or quinidine, which is not clinically significant in prophylactic dosing or with therapeutic administration. Bradycardia is commonly reported.^24,63,80 With prophylactic use, neither the PR interval nor the QRS complex is prolonged, but QT interval prolongation is reported.^33,63 Reports of torsade de pointes are rare, but the increase in QT interval and risk of torsade de pointes are increased when mefloquine is used concurrently with quinine, chloroquine, or most particularly, with halofantrine.^63,80,81,116 The long half-life of mefloquine means that particular care must be taken with therapeutic use of other antimalarials when breakthrough malaria occurs during mefloquine prophylaxis or within 28 days of mefloquine therapy to avoid potential drug–drug interactions. This risk would be expected to increase with acute overdose, although there is little clinical experience.

Mefloquine is commonly associated with neuropsychiatric side effects. During prophylactic use, 10% to 40% of patients experience insomnia and bizarre or vivid dreams and complain of dizziness, headache, fatigue, mood alteration, and vertigo.^98,113 Only 2% to 10% of these complications necessitate the traveler to seek medical advice or change normal activities.²⁴ Predisposing factors include a past history of neuropsychiatric disorders, recent prior exposure to mefloquine (within 2 months), previous mefloquine-related neuropsychiatric adverse effects, and previous treatment with psychotropics.¹⁰⁷ Women appear to be more likely than men to experience neuropsychiatric adverse effects.^107,113

The risk of serious neuropsychiatric adverse effects (convulsions, altered mental status, inability to ambulate due to vertigo, ataxia, or psychosis) during prophylaxis is estimated to be one in 10,600 but is reported to be as high as one in 200 with therapeutic dosing.^31,107 Seizures occur rarely with prophylaxis and therapeutic use. In many of these cases, there is a history of previous seizures, seizures in a first-degree relative, or other seizure risk factors. Other neuropsychiatric symptoms include dysphoria, altered consciousness, encephalopathy, anxiety, depression, giddiness, and agitated delirium with psychosis. Although there is a suggestion that the severity of neuropsychiatric events is dose dependent, there does not seem to be a correlation with serum or tissue concentrations.⁵⁶

The effect of mefloquine on the pancreatic potassium channel is much less than that of quinine, resulting in only a mild increase in insulin secretion.^32,33 Symptomatic hypoglycemia has not been reported as an effect of mefloquine alone in healthy individuals, but has occurred with concomitant use of ethanol and in a severely malnourished patient with acquired immune deficiency syndrome (AIDS).^10,33,63 In overdose, particularly when accompanied by ethanol use or starvation, hypoglycemia can be severe.

Rare events such as hypersensitivity reactions reported with prophylaxis include urticaria, alopecia, erythema multiforme, toxic epidermal necrolysis, myalgias, mouth ulcers, neutropenia, and thrombocytopenia.^81,98,103 It is unclear which, if any, would be significant after overdose. Acute respiratory distress syndrome was linked to therapeutic dosing in one case report.

In therapeutic use, mefloquine is associated with an increased incidence of stillbirth compared with quinine and a group of other antimalarials.⁸² Mefloquine was not, however, linked to an increased incidence of abortion, low birth weight, mental retardation, or congenital malformations. The implications of overdose in the absence of malaria are unknown, but fetal monitoring should be instituted.

The consequences of excessive dosing and overdose are not only severe but also prolonged and potentially permanent.

Management

In overdose, treatment is primarily supportive with monitoring for potential adverse effects. Decontamination with activated charcoal is indicated if the patient presents soon after the ingestion. Specific monitoring for ECG abnormalities, hypoglycemia, and liver injury should be provided. Pregnant patients should be followed with fetal monitoring. Because of mefloquine’s long half-life and potential for CNS accumulation, observation of asymptomatic patients for at least 24 hours is a reasonable approach. Central nervous system effects usually resolve within a few days, but persistent, permanent, and delayed-onset CNS effects are reported, so observation for full resolution of CNS effects would not be practical.

In 2 patients with kidney failure who received mefloquine, prophylactic hemodialysis did not remove mefloquine.²⁸ Given the large volume of distribution and high degree of protein binding of mefloquine, extracorporeal elimination techniques are unlikely to be effective.

In one case report, the severe neuropsychiatric manifestations of mefloquine were reversed with physostigmine, leading the authors to suggest a possible central anticholinergic mechanism. Physostigmine is not recommended as a routine treatment for mefloquine neuropsychiatric side effects.

Halofantrine

Because of erratic absorption, the potential for lethal cardiotoxicity, and concern for cross resistance with mefloquine, halofantrine is not presently recommended for malaria prophylaxis by the CDC.⁶

Pharmacokinetics and Toxicodynamics

See Table 55–3 for the pharmacokinetic properties of halofantrine.

Clinical Manifestations

The primary toxicity from therapeutic and supratherapeutic doses is prolongation of the QT interval and the risk of torsade de pointes and ventricular fibrillation.^81,109 Palpitations, hypotension, and syncope occur. First-degree atrioventricular (AV) block is common, but bradycardia is rare.⁸¹ Dysrhythmias are also likely in the context of combined overdose or combined or serial therapeutic use with other xenobiotics that cause QT interval prolongation, particularly mefloquine.⁵⁵ Because the QT interval duration is directly related to the serum halofantrine concentration, dysrhythmias should be expected in overdose.^24,81,107 Fifty percent of children receiving a therapeutic course of halofantrine will have a QT interval greater than 440 ms.¹⁰⁴

Other side effects, including nausea, vomiting, diarrhea, abdominal cramps, headache, and lightheadedness, which frequently occur in therapeutic use, are also expected in overdose.⁶³ Less frequently described side effects include pruritus, myalgias, and rigors. Seizures, minimal liver enzyme abnormalities, and hemolysis are described.^63,73 Whether these manifestations are related to halofantrine or to the underlying malaria is not clear.

Management

Management of patients with halofantrine overdose should focus on decontamination, supportive care, monitoring for QT interval prolongation, and treatment of any associated dysrhythmias. Based on rare case reports, non-overdose evidence, and known erratic absorption, observation of asymptomatic overdose patients for 24 hours before medical clearance would be a reasonable approach.

Lumefantrine

Lumefantrine is structurally similar to halofantrine. It is primarily used as a partner drug in the artemisinin-based combination therapy (ACT) artemether plus lumefantrine.

Little toxicity of lumefantrine alone or in combination is reported. Studies do not show QT interval prolongation or evidence of cardiac toxicity related to lumefantrine.³⁶ Cough and angioedema were described in one case. As in the case of all antimalarials, it is difficult to differentiate drug-related adverse events from those of malaria, comorbid diseases, or other ingested drugs, which confounds the study of potential complications.

4-AMINOQUINOLINES

The structurally related compounds chloroquine and amodiaquine were once used extensively for malaria prophylaxis. However, with the development of resistance, they are now used in fewer geographic regions. Amodiaquine is associated with a higher incidence of hepatic toxicity and agranulocytosis. In general, these xenobiotics have low toxicity when used in therapeutic doses. Because of its low toxicity, chloroquine remains the first-line drug for malaria prophylaxis and treatment in areas where Plasmodium spp remain sensitive.

Hydroxychloroquine is similar to chloroquine in therapeutic, pharmacokinetic, and toxicologic properties. The side effect profiles of the 2 are slightly different, favoring chloroquine use for malarial prophylaxis and hydroxychloroquine use as an antiinflammatory.^63,114 Hydroxychloroquine is used in the treatment of rheumatic diseases such as rheumatoid arthritis and lupus erythematosus. In animal studies, chloroquine is 2 to 3 times more toxic than hydroxychloroquine.⁵²

Piperaquine is structurally similar to chloroquine but is primarily used in conjunction with artemisinin compounds as a component of an ACT.

Antimalarial Mechanism

The 4-aminoquinolines interfere with the digestion of heme and hemozoin formation in a manner similar to that of the amino alcohols.³⁴

Chloroquine and Hydroxychloroquine

Pharmacokinetics and Toxicodynamics

See Table 55–3 for the pharmacokinetic properties of chloroquine. Oral chloroquine is rapidly and completely absorbed and is ultimately sequestered in many organs, particularly the kidney, liver, lung, and erythrocytes.^17,48

Chloroquine is slowly distributed from the blood compartment to the larger central compartment, leading to transiently high whole blood concentrations shortly after ingestion.^90,102 It is the initial high blood concentrations that are thought to be responsible for the rapid development of profound cardiorespiratory collapse typical of chloroquine toxicity. These early whole blood chloroquine concentrations correlate with death²⁷ and are better predictors of cardiovascular symptom severity than serum concentrations.⁷⁰ Unfortunately chloroquine concentrations are rarely rapidly available and thus unlikely to be useful for early bedside clinical decision making.

Pathophysiology

With structural similarity to quinine, the pathophysiologic mechanisms of chloroquine and hydroxychloroquine are also similar. Most notably, sodium and potassium channel blockade are the likely primary mechanisms of cardiovascular toxicity.¹¹⁶

Although less common in quinine toxicity, hypokalemia is extremely common in chloroquine overdose. The mechanism appears to be a shift of potassium from the extracellular to the intracellular space and not a true potassium deficit.^65,90,100

Clinical Manifestations

Similar to quinine, chloroquine has a narrow toxic-to-therapeutic ratio. Severe chloroquine poisoning is usually associated with ingestions of 5 g or more in adults, systolic blood pressure less than 80 mm Hg, QRS complex duration of more than 120 ms, ventricular fibrillation, hypokalemia, and serum chloroquine concentrations exceeding 25 µmol/L (8 mcg/mL).^26,93 Not surprisingly, suspected ingested doses do not always correlate with blood concentrations,⁷¹ but the suspected ingested dose still remains a potentially helpful historic predictor of the possibility for severe toxicity.

Symptoms usually occur within 1 to 3 hours of ingestion.⁹³ The range of symptoms associated with chloroquine toxicity is similar to that of quinine, but the frequencies of various manifestations differ, and other features such as cinchonism are uncommon. Nausea, vomiting, diarrhea, and abdominal pain occur less commonly than with quinine.^49,63 In contrast, respiratory depression is common, and apnea, hypotension, and cardiovascular compromise can be precipitous.⁴⁹

The cardiovascular effects of chloroquine and hydroxychloroquine are similar to those of quinine, including QRS complex prolongation, AV block, ST and T wave depression, increased U waves, and QT interval prolongation. Hypotension is more prominent in chloroquine toxicity than with quinine.⁴⁹

Significant hypokalemia in chloroquine toxicity is invariably associated with cardiac manifestations.⁴⁹ In fact, the extent of hypokalemia is a good indicator of the severity of chloroquine overdose²⁶ and mortality rate.⁷⁰

Neurologic manifestations include CNS depression, dizziness, headache, and convulsions.⁴⁶ Rarely, dystonic reactions occur. Transient parkinsonism is also reported after excessive dosing.

Ophthalmic manifestations are infrequent in acute chloroquine toxicity and transient in nature.^49,63 More severe and irreversible vision and hearing changes are described in association with the chronic use of chloroquine and hydroxychloroquine as antiinflammatories.^63,78 Myopathy, neuropathy, and cardiomyopathy also occur when used for that purpose.⁸ Dermatologic findings and hypersensitivity reactions are similar to those associated with quinine.³³ Likewise, red blood cell (RBC) oxidant stress from chloroquine results in hemolysis in patients with G6PD deficiency (Chap. 20).

Acute hydroxychloroquine toxicity is similar to chloroquine toxicity.⁵² Side effects from therapeutic doses include nausea and abdominal pain; hemolysis in G6PD-deficient patients; and, rarely, retinal damage, sensorineural deafness, and hypoglycemia. Hypersensitivity reactions, including myocarditis and hepatitis, are described.

Management

Aggressive supportive care is recommended, including oxygen, cardiac and hemodynamic monitoring, and large-bore IV access, and serial blood glucose concentrations. Despite reported rapid absorption, one series reported delayed peak blood concentrations in some patients,⁷⁰ opening the possibility of a potential benefit for early GI decontamination methods. Orogastric lavage is recommended for life-threatening ingestions presenting early, but there is little evidence of efficacy. Activated charcoal adsorbs chloroquine well, binding 95% to 99% when administered within 5 minutes of ingestion.⁵⁹ The frequent development of precipitous cardiovascular and CNS toxicity should be anticipated before initiating any type of GI decontamination.

Early aggressive management of severe chloroquine toxicity decreases the mortality rate.⁹³ This includes early endotracheal intubation and mechanical ventilation. Evidence suggests that barbiturates are not desirable for induction in patients with chloroquine overdose. When thiopental was used to facilitate intubation, its use immediately preceded sudden cardiac arrest in 7 of 25 patients after chloroquine overdose.²⁷ Regardless of induction agent, an adequate FiO₂, tidal volume, and ventilatory rate should be ensured.

Although theoretically any direct-acting vasopressor would be beneficial in the setting of hypotension not responsive to fluid resuscitation, epinephrine is the vasopressor most extensively studied and is therefore the vasopressor of choice. High doses of epinephrine were used in the original studies describing the benefits of early mechanical ventilation and the administration of diazepam and epinephrine in chloroquine poisoning.^93,94 The epinephrine doses used in these studies are still recommended today.^93,94 The recommended dose is 0.25 mcg/kg/min, increasing by 0.25 mcg/kg/min until an adequate systolic blood pressure (>90 mm Hg) is achieved.^30,69,93,94 ­Clinicians should be mindful that high doses of epinephrine could exacerbate preexisting hypokalemia.

The use of diazepam to augment the treatment of dysrhythmias and hypotension is a unique use of this drug. Initial observations with regard to patients with mixed overdoses of chloroquine and diazepam suggested less cardiovascular toxicity and a potential benefit of high-dose diazepam.^27,65 Animal and human studies that followed also showed a potential benefit.^30,93,94 When early mechanical ventilation was combined with the administration of high-dose diazepam and epinephrine in patients severely poisoned by chloroquine, a dramatic improvement in survival compared with historical control participants (91% vs 9% survival) occurred.⁹³ Studies in moderately poisoned patients failed to show similar benefit,²⁶ and a rat model failed to show an inotropic effect. Although the definitive study has yet to be done, high-dose diazepam therapy (2 mg/kg IV over 30 minutes followed by 1–2 mg/kg/day for 2–4 days) is recommended for serious toxicity. Diazepam or an equivalent benzodiazepine should also be used to treat seizures and for sedation.

The mechanism for a potential benefit of diazepam is unclear, but multiple theories have been postulated: (1) a central antagonistic effect, (2) an anticonvulsant effect, (3) an antidysrhythmic effect by an electrophysiologic action inverse to chloroquine, (4) a pharmacokinetic interaction between diazepam and chloroquine, and (5) a decrease in chloroquine-induced ­vasodilation^65,90,93,94 (Antidotes in Depth: A26).

The use of sodium bicarbonate for correction of QRS complex prolongation is also controversial. Although alkalinization would be expected to counteract the effects of sodium channel blockade, it could also exacerbate preexisting hypokalemia. Although case reports describe the successful use of sodium bicarbonate in conjunction with xenobiotics for massive hydroxychloroquine overdose, no clinical trials have been performed. Before using sodium bicarbonate in the setting of chloroquine toxicity, clinicians should evaluate the overall clinical status of the patient, including the suspected degree of cardiac toxicity and severity of hypokalemia. In the setting of normal potassium, sodium bicarbonate is a reasonable intervention to counteract QRS complex prolongation.

Hypokalemia in the setting of chloroquine overdose correlates with the severity of the toxicity.^26,65 Potassium replacement in this setting is, again, controversial because it has not been shown that potassium supplementation will improve cardiac toxicity. In fact, several reports suggest a possible protective effect of hypokalemia in acute chloroquine toxicity.^26,65,90 This should be balanced against the fact that severe hypokalemia can itself result in lethal dysrhythmias and data suggesting severe hypokalemia (<1.9 mEq/L) is associated with severe, life-threatening ingestion.^24,49,65,102 Hypokalemia could not be directly attributed as the cause of death in most cases, however.²⁶ Based on the available evidence, potassium replacement for severe hypokalemia would be a reasonable intervention, but it is essential to anticipate rebound hyperkalemia as chloroquine toxicity resolves and redistribution of intracellular potassium occurs. Cases of hyperkalemia-related complications are reported after aggressive potassium supplementation.^52,65

Because chloroquine and hydroxychloroquine have high volumes of ­distribution and significant protein binding, enhanced elimination procedures are not beneficial.^17,49 There is limited experience with lipid emulsion therapy in the setting of chloroquine poisoning; thus its use is not recommended (Antidotes in Depth: A23).

Piperaquine

See Table 55–3 for the pharmacokinetic properties of piperaquine.

Piperaquine was used extensively in China and Indonesia as an antimalarial until the development of piperaquine-resistant strains led to the use of better alternatives. Piperaquine has since undergone a rediscovery as a viable combination with artemisinin derivatives in ACT DP (dihydroartemisinin-piperaquine) therapy. Animal studies show piperaquine to be substantially less toxic than chloroquine. Cardiovascular toxicity with piperaquine requires cumulative doses 5 times higher than that of chloroquine. Hepatotoxicity occurs after chronic exposure in animals. In a human study, no ­significant changes in ECG or in serum glucose concentration, and no postural hypotension occurred after therapeutic doses of DP.

Patients with overdose should be managed with supportive measures and expectant observation, including cardiovascular and CNS monitoring.

Amodiaquine

Amodiaquine has pharmacologic properties similar to others in the 4-aminoquinolone family. It is rapidly absorbed from the GI tract and hepatically metabolized by CYP2C8 into its active antimalarial metabolite, desethylamodiaquine.¹¹⁸

Amodiaquine fell out of favor as a prophylactic treatment as a result of serious and sometimes fatal liver and bone marrow toxicity,¹⁰⁷ but is still a component of one of 5 ACTs recommended by the WHO for treatment of active malarial infection. Hypersensitivity reactions (hepatitis and neutropenia) described in prophylactic use are uncommon with therapeutic use.^21,118 Reports of amodiaquine toxicity suggest that involuntary movements, muscle stiffness, dysarthria, syncope, and seizures can occur.^2,49 There is no overdose experience reported. Aggressive symptomatic and supportive care, expectant observation, including cardiovascular and CNS monitoring, should be provided for possible poisoning.

8-AMINOQUINOLINES

Primaquine

Primaquine and its related compounds are the only drugs licensed for the prevention of P. ovale and P. vivax relapse caused by hepatic hypnozoites (Fig. 55–1). Studies using primaquine in the early 1950s led to the discovery of G6PD deficiency after those with the disease developed hemolysis when administered the drug.¹⁴ Glucose-6-phosphate dehydrogenase deficiency actually offers some protection against malaria because the erythrocytes of those with the disease rupture under the increased oxidative stress of the parasite’s metabolism before completion of the erythrocytic cycle. Primaquine is making a resurgence in some countries for P. falciparum treatment as a gametocytocide to reduce transmission in campaigns to eradicate malaria from these regions.⁵⁰

Antimalarial Mechanism

The antimalarial action of primaquine is poorly understood but thought to be related to increasing the oxidative stress of erythrocytes,¹¹⁵ obstructing proper parasitic development.

Pharmacokinetics and Toxicodynamics

See Table 55–3 for the pharmacokinetic properties of primaquine. Metabolism is primarily hepatic, using multiple enzyme systems, with CYP2D6 playing a prominent role.⁷ The parent compound is metabolized to reactive intermediates that are thought to mediate both its antimalarial and hemolytic effects.

Pathophysiology

Primaquine blocks sodium channels both in vitro and in animal models.^49,116 Significant cardiovascular toxicity has not been reported, although experience with primaquine overdose is limited primarily to case reports.

The predominant clinical toxicity of primaquine relates to its ability to cause RBC oxidant stress and resultant hemolysis or methemoglobinemia. Methemoglobinemia and hemolysis can occur in normal individuals given high doses as well as those with G6PD deficiency.^63,107

The major complication of primaquine in therapeutic use is hemolysis in G6PD-deficient individuals.³² Primaquine is contraindicated in pregnant women because of the risk of methemoglobinemia or hemolysis in the fetus. Reversible bone marrow suppression can occur.

Clinical Manifestations

Gastrointestinal irritation is common and dose related.

The extent of hemolysis in G6PD-deficient individuals depends on the extent of enzyme activity, those with greater enzyme activity having less severe hemolysis than those with less enzyme activity (Chap. 20). Other variables include the dose of primaquine and comorbid conditions, such as infection, liver disease, and administration of other drugs with hemolytic activity.

Overdose with primaquine is rarely reported, and unintentional ­overdoses have led to methemoglobinemia requiring IV methylene blue (Chap. 124).¹⁰⁷ Acute liver failure has occurred after unintentional overdose, and fatal hepatotoxicity is described in animal models.⁶¹

Management

Therapy should be directed at minimizing absorption with appropriate decontamination, and diagnosing then treating significant methemoglobinemia or hemolysis. Because of structural similarities with other quinolone antimalarials and animal model evidence of sodium channel blockade, ­cardiovascular toxicity should be anticipated with continuous monitoring and resuscitative interventions initiated as needed.

Activated charcoal is a reasonable early intervention (Antidotes in Depth: A1). Methylene blue (Chap. 124 and Antidotes in Depth: A43) is recommended for patients who are symptomatic with methemoglobinemia. Treatment of hemolysis necessitates avoiding further exposure to primaquine and possibly exchange transfusion in severe cases. Adequate hydration should be ensured to protect against hemoglobin-induced acute kidney injury. Urinary alkalinization with sodium bicarbonate is controversial in this setting but is not routinely recommended because it has not been proven to be superior to aggressive sodium chloride 0.9% hydration alone (Antidotes in Depth: A5).

Although no clinical studies have been performed, the large volume of distribution of primaquine makes it an unlikely candidate for benefit from extracorporeal removal.

ENDOPEROXIDES

Artemisinin and Derivatives

The medicinal value of natural artemisinin, the active ingredient of Artemisia annua (sweet wormwood or quinghao), has been known for thousands of years. Its antimalarial properties were first recognized by ­Chinese herbalists in A.D. 340, but the primary active component of qinghaosu, now known as artemisinin, was not isolated until 1974.^8,114 Artemisinin and its semisynthetic derivatives, artesunate, artemether, arteether, and dihydroartemisinin, are the most potent and rapidly acting of all antimalarials. They were introduced in the 1980s in China for the treatment of malaria, and since then millions of doses have been used in Asia and Africa. Because of their extremely short half-lives, the artemisinins are now used in combination with drugs with longer half-lives to delay or prevent the emergence of resistance. Artemisinin-based combination therapies are currently recommended by the WHO for the treatment of uncomplicated malaria¹¹⁸ but only one has been licensed for use in the United States; artemether and lumefantrine. Five artemesin-based combination therapies (ACT) are currently recommended by the WHO. These include artemether plus lumefantrine, artesunate plus mefloquine, artesunate plus pyrimethamine–sulfadoxine, artesunate plus amodiaquine, and dihydroartemisinin and piperaquine.

Antimalarial Mechanism

The artemisinins have a unique structure containing a 1,2,4-trioxane ring. The endoperoxide linkage within this ring is cleaved when it comes into contact with ferrous iron, releasing free radicals that destroy the parasite.¹ Artemisinin is the only known natural product to contain a 1,2,4-trioxane ring, and although chemical synthesis is possible, thus far it has not been financially advantageous.

Pharmacokinetics and Toxicodynamics

See Table 55–3 for the pharmacokinetic properties of artemisinin. ­Artemisinin and its derivatives are rapidly metabolized to the primary active metabolite dihydroartemisinin.⁶⁸ Similar to its proposed efficacy, the toxicity of artemisinin is thought to be a result of the ability of the trioxane molecular core to form intracellular free radicals, particularly in the presence of heme. In animals, damage to brain stem nuclei is consistently produced after ­prolonged, high-dose, and parenteral administration.¹⁰⁷ Sustained CNS exposure from slowly absorbed or eliminated artemisinins is considered markedly more neurotoxic than intermittent brief exposure that occurs after oral dosing. Embryonic loss is also observed in animals.

Clinical Manifestations

In contrast to the experience with animals, the general theme throughout the literature suggests that these drugs have a very low incidence of side effects. This is consistent with the belief that long-term, rather than short-term, peak concentrations are primarily responsible for toxicity.³⁵ Uncommon side effects include nausea, vomiting, abdominal pain, diarrhea, and dizziness. Few large-scale trials powered to detect rare but possibly significant toxicity have been performed.

Prospective studies have failed to identify adverse neurologic outcomes.^58,107 Rare reports of adverse CNS effects during therapeutic use suggest the possibility of CNS depression, seizures, or cerebellar symptoms after intentional self-poisoning. In children with cerebral malaria, a higher incidence of seizures and a delay to recovery from coma were noted in a comparison with quinine.¹¹² No neurologic difference was noted in long-term follow-up. In an artemether–quinine comparative trial of adults with severe malaria, recovery from coma was also prolonged in the artemether group.¹¹⁰ Rare patients receiving an artemisinin derivative in 2 other studies experienced transient dizziness or cerebellar signs.⁸⁸ Most recovered within days. One patient in each study had prolonged symptoms lasting 1 month and 4 months, respectively, but both ultimately recovered.

When serial ECGs were obtained, a small but statistically significant decrease in heart rate was noted coincident with peak drug concentrations.⁷² In one therapeutic trial, 7% of adult patients receiving artemether had an asymptomatic QT interval prolongation of at least 25%.¹¹⁰ Changes in the QRS complex are not reported.

Although uncommon, neutropenia, reticulocytopenia, anemia, eosinophilia, and elevated aminotransferases are reported.¹⁰⁷ Acute ACT overdose is rarely reported outside large population-based studies. Morbidity and mortality of overdose are frequently difficult to differentiate from those of the underlying malarial disease and coingestants.

NAPHTHOQUINONES

Atovaquone

Atovaquone is a structural analog of ubiquinone, or coenzyme Q, a mitochondrial protein involved in electron transport.⁹ Atovaquone disrupts the protozoal mitochondrial membrane potential, leading to inhibition of several parasite-specific enzymes, ultimately leading to the inhibition of pyrimidine synthesis, which is necessary for protozoal survival and replication. Based on its beneficial side effect profile, the CDC recommends the combination atovaquone–proguanil for treatment of chloroquine-resistant malaria. The price of this combination as well as the variable bioavailability of atovaquone limits its use in less affluent countries.

Atovaquone alone, primarily used to treat Pneumocystis jiroveci in patients with AIDS, is relatively well tolerated.⁸⁴ Side effects include maculopapular rash, erythema multiforme (rarely), GI complaints, and mild aminotransferase elevations. Three cases of 3- to 42-fold overdose or excess dosing are reported.²⁵ No symptoms occurred in one case (at 3 times therapeutic serum concentration). Rash occurred in another, and in the third case, methemoglobinemia was attributed to a simultaneous overdose of dapsone.

When used to treat malaria, atovaquone-proguanil side effects include abdominal pain, nausea, vomiting headache, diarrhea, anorexia, and dizziness.⁹ This combination is also associated with elevated aminotransferases⁸⁹ and hepatosplenomegaly.⁹ Reported overdose has caused little serious toxicity.¹⁰⁷

Atovaquone is reported to have extensive enterohepatic cycling, with 94% of the drug eliminated in the feces.^9,66 Although there is no evidence, multiple-dose activated charcoal is a reasonable intervention in selected overdose patients.

ANTIFOLATES AND ANTIBIOTICS

Antimalarial Mechanism

Proguanil, pyrimethamine, and the antibiotic trimethoprim interfere with malarial folate metabolism by inhibiting dihydrofolate reductase at concentrations far lower than that required to produce comparable inhibition of mammalian enzymes.¹¹⁴ Dapsone and sulfonamide antibiotics also disrupt malarial folate metabolism, but by inhibiting a different enzymatic reaction—dihydropteroate synthase. Slow onset of action and concerns for the development of resistance have led to the use of these medications in synergistic combinations leading to inhibition of folate metabolism at 2 different sites.

Pharmacokinetics and Toxicodynamics

See Table 59–3 for the pharmacokinetic properties of pyrimethamine, proguanil, and dapsone.

Proguanil’s active metabolite, cycloguanil, is primarily responsible for its antimalarial activity. Both the parent drug and active metabolite share substantial renal excretion, making renal insufficiency a risk factor for toxicity.⁵¹ Dapsone is chiefly metabolized by CYP2C19 to dapsone hydroxylamine.¹⁰⁸ These hydroxylamine metabolites have a long half-life, partially because of enterohepatic recirculation, and concentrate in erythrocytes leading to oxidant stress resulting in methemoglobinemia and hemolysis. Cimetidine competes for the same CYP enzymes, decreasing methemoglobin levels during therapeutic ­dapsone dosing⁹² presumably by shunting dapsone metabolism to alternate nontoxic pathways.

Clinical Manifestations

The side effects of proguanil during prophylaxis include nausea, diarrhea, and mouth ulcers.⁶³ Because of the interference with folate metabolism, megaloblastic anemia is a rare but potential complication. Megaloblastic bone marrow toxicity is reported in patients with chronic kidney disease.¹⁰⁷ Folate supplementation is recommended in pregnancy and CKD to avoid this complication.³¹ Rarely, neutropenia, thrombocytopenia, rash, and alopecia are also noted. In a single case report, hypersensitivity hepatitis was described.³¹

Overdose of pyrimethamine alone is rare. In children, it results in nausea, vomiting, a rapid onset of seizures, fever, and tachycardia.^3,49 Blindness, deafness, and developmental delay have followed. It is unclear whether the chronic neurologic deficits described in case reports are attributable to direct ­toxicity of pyrimethamine on the CNS or to complications of toxicity such as status epilepticus. Chronic high dose use is associated with a megaloblastic anemia and bone marrow suppression, requiring folate replacement.³

The sulfonamides, including the sulfone dapsone, have a long history of causing idiosyncratic reactions, including neutropenia, thrombocytopenia, eosinophilic pneumonia, aplastic anemia, neuropathy, and hepatitis.^63,107 Rare occurrence of life-threatening erythema multiforme major and toxic epidermal necrolysis, associated with pyrimethamine–sulfadoxine prophylaxis, has limited the use of this combination.

Acute ingestion of dapsone results in nausea, vomiting, and abdominal pain.⁴⁹ After overdose, dapsone produces RBC oxidant stress, leading to methemoglobinemia and, to a much lesser extent, sulfhemoglobinemia through formation of an active metabolite (Chap. 124).^23,64 Hemolysis may be either immediate or delayed. Dapsone, in particular, is known for its tendency to cause prolonged methemoglobinemia. Other symptoms, particularly tachycardia, dyspnea, dizziness, visual hallucinations, seizure, syncope, and coma resulting from end-organ hypoxia, can occur. Additional effects described in overdose include hepatitis and peripheral neuropathy.⁴⁹

Management

Neural tube defects are associated with the use of folic acid antagonists, thus folate supplementation is reasonable in reproductive age women exposed to these agents. Folinic acid (leucovorin) would be a reasonable intervention after an overdose of proguanil or pyrimethamine (Antidotes in Depth: A12). Other efforts should include supportive care.

After dapsone ingestion, clinically significant methemoglobinemia should be treated with methylene blue (Chap. 124 and Antidotes in Depth: A43). The long half-life of dapsone and its metabolites often make repetitive doses of methylene blue necessary. The patient’s clinical status is more important than a single methemoglobin level for determining treatment interventions. There is no antidote for sulfhemoglobinemia, but it constitutes an insignificant portion of total hemoglobin.

Multiple-dose activated charcoal is recommended for patients with a dapsone overdose and no contraindicators.⁶⁴ Exchange transfusion is a reasonable intervention for patients who fail to respond to methylene blue. Hemodialysis decreased methemoglobinemia concentrations in case reports but subsequent rebound dapsone concentrations were observed.⁷⁹ Continuous veno-venous hemofiltration increased dapsone clearance 3-fold in a single case report. These extracorporeal methods of removal are not routinely recommended. Hyperbaric oxygen has been used in case reports as an adjunct to methylene blue in the treatment of methemoglobinemia but is not routinely recommended (Antidotes in Depth: A43).

Cimetidine supplementation is a reasonable intervention after dapsone overdose. Other antioxidants, ascorbic acid and vitamin E, have been used to treat methemoglobinemia¹² but are not routinely recommended because their slow onset of action makes a benefit unlikely.

FUTURE DIRECTIONS

Shared cytochrome P450 metabolic pathways and genetic polymorphisms are increasingly recognized as contributing factors in drug–drug interactions and toxicity. The clarification of various antimalarial metabolic pathways has led to concern for potential toxicity due to these interactions. The clinical relevance of these interactions is unclear, however. Genetic polymorphism is described in the metabolism of proguanil and dapsone and may be a contributing factor to the hypersensitivity reactions noted with dapsone.^53,91 Table 55–3 highlights the known potentially significant metabolic interactions of antimalarials.