57: Antibacterials, Antifungals, and Antivirals

Antimicrobials, including antibacterials, antifungals, and antivirals, have significantly improved the clinical care of infected patients since the introduction of penicillin in the 1940s. The development of antimicrobial-resistant strains of these pathogens has continually expanded the number of antimicrobials necessary, and this has increased the overall potential for toxicity after use. Fortunately, toxicity due to acute overdose is limited and chronic therapeutic doses are safe in the majority of patients.

Most adverse effects related to antimicrobials occur as a result of iatrogenic complications rather than intentional overdose. The diverse origins of these complications include dose, route and decision errors, allergic reactions, adverse effects, and interactions. Prevention, in the form of process improvements and information regarding populations at risk for adverse effects, is continually required to minimize these untoward events. Dosing errors are prominent in neonates and infants, necessitating care and constant diligence on the part of health care professionals.

Antimicrobials are more commonly associated with allergic reactions than are other xenobiotics. The reason for this is unclear, but it may be a result of their high frequency of use, repeated intermittent prescriptive use, or environmental contamination. A complete allergy history is essential to minimize these adverse events in patients being considered for antimicrobial therapy.

Many adverse effects attributed to antimicrobials are difficult to predict even when given patient and population specific parameters. In some cases, an excipient is responsible for the adverse effect, as recognized with the adverse effects found in patients after the use of procaine penicillin G. Antimicrobials are involved in many common and severe xenobiotic interactions, primarily through the inhibition of metabolic enzymes. Patients being considered for antimicrobial therapy should be carefully assessed for the use of concomitant therapies, both prescription and nonprescription which may be pharmacokinetically or pharmacodynamically affected by the chosen antimicrobial.

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 57–1 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 the therapeutic mechanisms.

Aminoglycosides

Aminoglycoside that are in current use in the United States include amikacin, gentamicin, kanamycin, neomycin, paromomycin, streptomycin, and tobramycin.

Because aminoglycosides are only available in parenteral, topical, and ophthalmic forms, overdoses are almost exclusively the result of dosing errors. Fortunately, overdoses are rarely life threatening, and most patients can be safely managed with minimal intervention.^24,121 The adverse effects of aminoglycosides are generally class based, although subtle differences may exist in the potency with which the adverse effects occur (Table 57–2).

Large intravenous doses of aminoglycosides are both sufficiently safe and effective for use in single daily doses.⁶ Rarely, acute aminoglycoside overdose results in nephrotoxicity, ototoxicity, or vestibular toxicity.^117,141 In one reported case, postmortem analysis confirmed complete loss of hair cells in the inner and outer cochlear (Chap. 26).

Aminoglycosides can exacerbate concomitant neuromuscular blockade, particularly at times corresponding to high peak serum aminoglycoside ­concentrations (Chap. 69).¹⁷¹ This is caused by inhibiting presynaptic calcium channels, thereby inhibiting the release of acetylcholine from presynaptic nerve terminals. Risk factors for enhanced neuromuscular blockade include patients with abnormal neuromuscular junction function, such as those with myasthenia gravis and botulism.

Adverse Effects Associated with Therapeutic Use.

Adverse effects, including nephrotoxicity and ototoxicity, correlate more closely with ele­vated trough serum concentrations than with elevated peak concentrations.^108,149 Less common adverse effects associated with chronic use include electrolyte abnormalities, allergic reactions, hepatotoxicity, anemia, granulocytopenia, thrombocytopenia, eosinophilia, retinal toxicity, reproductive dysfunction, tetany, and psychosis.^{55,112,126,217,233} When aminoglycosides are administered at high doses or during once-daily ­dosing, sepsislike chills and malaise may occur that can be the result of excipients delivered during the infusion.⁴⁶

Nephrotoxicity. 

The mechanism of nephrotoxicity and ototoxicity is incompletely understood, but appears to include the formation of reactive oxygen species in the presence of iron. Mitochondrial respiration is inhibited, lipid peroxidation occurs, and stimulation of glutamate activated N-methyl-d-aspartate (NMDA) receptors may play a role.^96,243 The incidence of nephrotoxicity with aminoglycoside therapy is estimated at 5% to 10%.⁹ Although the aminoglycosides are almost completely excreted prior to biotransformation in the kidney, a small fraction of filtered aminoglycoside is transported by absorptive endocytosis across the apical membrane of proximal tubular cells where it becomes sequestered within lysosomes. The aminoglycoside then binds to and destroys phospholipids contained on brush border membranes in the proximal renal tubule.⁹

When this happens, acute tubular necrosis occurs after 7 to 10 days of standard-dose therapy. Laboratory abnormalities include granular casts, proteinuria, elevated urinary sodium, and increased fractional excretion of sodium. Usually acute kidney injury (AKI) that results is reversible; however, irreversible toxicity has been reported. Functionally, the injury occurs days prior to elevations in serum creatinine concentration, and for this reason a delay in diagnosis is common.²⁰⁴ 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.^9,152 Because the uptake of aminoglycosides into organs is saturable, appropriate once-daily high-dose regimens are less problematic than several lesser doses given in a single day.

Ototoxicity. 

Ototoxicity can occur after acute or prolonged exposure to aminoglycosides.²⁰⁶ 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.³ 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 57–2 details the relative characteristic toxicity of various aminoglycosides.

Full-tone audiometric testing may first show high-frequency hearing loss, which may subsequently progress. Given the inability of cochlear hair cells to regenerate, all hearing loss that develops is permanent. After early diagnosis of vestibular dysfunction, patients may improve after discontinuation of the xenobiotic. Simultaneous administration of other ototoxic xenobiotics enhances the ototoxicity of aminoglycosides (Chap. 26).

Withdrawal of the offending xenobiotic is indicated in patients with either nephrotoxicity or ototoxicity caused by an aminoglycoside antibiotic. Supportive care is the mainstay of therapy. Experimental treatments in animal models include the use of deferoxamine, glutathione, and NMDA-receptor antagonists in an attempt to chelate and or detoxify a reactive intermediate.^165,221 The antibiotic ticarcillin forms a renally eliminated complex with aminoglycosides to provide protection against tobramycin-induced AKI. In humans, ticarcillin removes 50% more tobramycin in 48 hours than in two sessions of hemodialysis.⁷² However, ticarcillin therapy is generally of limited value because in most instances the serum concentration of the aminoglycoside has decreased before any therapeutic measures can be used.

Penicillins

Penicillin is derived from the fungus Penicillium and many semisynthetic derivatives have clinical utility. Penicillins, as a class, contain a 6-aminopenicillanic acid nucleus, composed of a β-lactam ring fused to a five-member thiazolidine ring. Classic available penicillins include penicillin G, penicillin V, and the antistaphylococcal penicillins (nafcillin, oxacillin, cloxacillin, and dicloxacillin). Penicillins developed to enhance the spectrum of antibiotic efficacy, particularly against Gram-negative bacilli, include the second generation penicillins (ampicillin, amoxicillin, bacampicillin, and mezlocillin), third generation penicillins (carbenicillin and ticarcillin), and fourth-generation penicillins (piperacillin). Table 57–1 lists the pharmacologic mechanism of penicillins.

Acute oral overdoses of penicillin-containing xenobiotics are usually not life threatening.²²⁶ The most frequent complaints following acute overdose are nausea, vomiting, and diarrhea.

Seizures occur in persons given large intravenous or cerebral intraventricular doses of penicillins.^113,123,147 More than 50 million units intravenously in less than 8 hours are generally required to produce seizures in adults.²⁰⁹ Penicillin induced seizures appear to be mediated through the picrotoxin-binding site on the neuronal chloride channel near the γ-aminobutyric acid (GABA) binding site (Chap. 14). Binding of the penicillin produces an allosteric change in the receptor that prevents GABA from binding, resulting in a relative lack of inhibitory tone.⁵⁸ Penicillin analogs (such as imipenem) also cause seizures, presumably through a similar mechanism.

The treatment of patients who develop penicillin induced seizures include GABA agonists such as the benzodiazepines. Patients who receive an intraventricular overdose may require cerebrospinal fluid exchange or perfusion to attenuate seizure activity (Special Considerations: SC3).¹²³ There are rare reports of hyperkalemia resulting in electrocardiographic abnormalities after the rapid intravenous infusion of potassium penicillin G to patients with CKD and amoxicillin overdose resulting in frank hematuria and AKI.^32,85

Adverse Effects Associated with Therapeutic Use.

Penicillins are associated with a myriad of adverse effects after therapeutic use, the most common of which are allergic reactions. Penicillins are commonly implicated in immune-related reactions such as bone marrow suppression, cholestasis, hemolysis, interstitial nephritis, and vasculitis.^7,83,103,220 Rare effects include pemphigus after penicillin use and corneal damage after the use of methicillin.^20,250

Acute Allergy.

Penicillins are the pharmaceuticals most commonly implicated in the development of acute anaphylactic reactions. Anaphylactic reactions are severe, life-threatening, immune-mediated (immunoglobulin E {IgE}) reactions involving multiple organ systems that typically occur immediately after exposure. Table 57–3 lists the classifications of anaphylactic reactions. Anaphylaxis to penicillin typically occurs after IgE antibody formation, which requires prior exposure. Life-threatening clinical manifestations include angioedema, tongue and airway edema, bronchospasm, bronchorrhea, dysrhythmias, cardiovascular collapse, and cardiac arrest.⁷³ The pathophysiology of systemic anaphylaxis is complex and involves multiple pathways. IgE antibodies are cross linked on the surface of mast cells and basophils, resulting in local and systemic release of preformed mediators of anaphylactic response, including leukotrienes C₄ and D₄, histamine, eosinophilic chemotactic factor, and other vasoactive substances, such as bradykinin, kallikrein, prostaglandin D₂, and platelet-activating factor (Fig. 57–1).

The incidence of penicillin hypersensitivity is 5% overall, with 1% of penicillin reactions resulting in anaphylaxis. The risk for a fatal hypersensitivity reaction after penicillin administration is two in 100,000 (0.002%) patient exposures.²⁴¹ 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. Initial therapy for anaphylaxis includes epinephrine 0.01 mg/kg (≤ 0.5 mg) given as 1:1000 (1 mg/mL) dilution intramuscularly (IM) every 10 to 20 minutes. Epinephrine bronchodilates and increases cardiac output through β-adrenergic receptor stimulation. In addition, β-adrenergic receptor stimulation results in decreased peripheral vascular tone. Oxygen and inhaled β₂-adrenergic agonists are warranted in severe cases, as are corticosteroids. H₁-receptor antagonists may be sufficient in patients with mild allergic reactions who do not have pulmonary manifestations or airway concerns.

H₂-receptor antagonism as a treatment for anaphylaxis is controversial. H₂-receptors, when stimulated in the peripheral vasculature, cause vasodilation; in the heart, they cause positive inotropy, positive chronotropy, and coronary vasodilation; and in the lung, they cause increased mucus production.¹⁹⁹ Theoretically, H₂-receptor antagonists can lead to a decrease in myocardial function at a time when H₁-receptor stimulation is causing hypotension, coronary vasoconstriction, and bronchospasm. However, in vitro and animal models demonstrate decreases in coronary circulation and decreases in the overall anaphylactic response following administration of H₁ blockers.¹⁵ All H₂-receptor antagonists are useful for the treatment of pruritus and flushing after acute allergic reactions involving the skin.^15,151 Cimetidine use following anaphylaxis may result in clinical improvement, particularly hypotension and tachycardia.^64,251 Available data indicate that treatment of anaphylaxis using H₂-receptor antagonists should only be considered when other therapies have failed and the patient is adequately H₁-receptor antagonized. Finally, glucagon may be of some benefit, particularly in patients who are maintained on β-adrenergic antagonists (Antidotes in Depth: A18).

Amoxicillin-Clavulanic Acid and Hepatitis.

If cholestatic hepatitis develops, it occurs 1 to 6 weeks after initiation of therapy with amoxicillin-clavulanate.⁸ The incidence of hepatotoxicity typically is estimated at 1.1 to 2.7 per 100,000 prescriptions.⁸² The mechanism of hepatotoxicity is not clear, but may be related to clavulanate, a β-lactamase inhibitor used to prevent the bacterial destruction of β-lactam antimicrobials, or one of its metabolites. Treatment is supportive and clinical findings typically resolve after the discontinuation of therapy. However, prolonged hepatitis, ductopenia (vanishing bile duct syndrome), and pancreatitis rarely occur.^48,184 Behavioral disturbances with disorientation, agitation, and visual hallucinations temporally related to use are also reported.¹⁷

Hoigne Syndrome and Jarisch-Herxheimer Reaction.

The most common adverse effects occurring after administration of large intramuscular or intravenous doses of procaine penicillin G are the Hoigne syndrome and the Jarisch-Herxheimer reaction.^110,146 The Hoigne syndrome is characterized by extreme apprehension and fear, illusions, or hallucinations; changes in auditory and visual perception, tachycardia, systolic hypertension, and, occasionally, seizures that begin within minutes of injection.²⁴⁰ These effects occur in the absence of signs or symptoms of anaphylaxis. The cause of this syndrome is unknown. 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.^200,211,236 Hoigne syndrome is six times more common in men than in women.²¹⁴ The reason for this increased prevalence is unclear, but autosomal dominance and influences of prostaglandin and thromboxane A₂ activity in this population may be responsible.¹²

The Jarisch-Herxheimer reaction is a self-limited reaction that develops within a few hours of antibiotic therapy for the treatment of spirochetal diseases such as syphilis or Lyme disease. Myalgias, chills, headache, rash, and fever spontaneously resolve within 18 to 24 hours, even with continued antibiotic therapy.²¹⁰ The pathogenesis of this reaction is likely either endotoxin induced from the lysed spirochete or cytokine elevation.¹⁷⁷ Antiinflammatory medications and immune modulators may offer some relief, but the optimal treatment is still unclear.

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, cephalexin, cephapirin, and cephradine. Second generation cephalosporins include cefaclor, cefamandole, cefonicid, cefotetan, cefoxitin, cefprozil, and cefuroxime. Third generation cephalosporins include cefdinir, ceftazidime, cefixime, ceftibuten, cefoperazone, ceftizoxime, cefotaxime, ceftriaxone, and cefpodoxime. The fourth generation cephalosporin is cefepime and the fifth generation cephalosporin is ceftaroline.

Effects occurring after acute overdose of cephalosporins resemble those occurring with penicillins. Some cephalosporins also have epileptogenic potential similar to penicillin.²⁴⁴ Case reports demonstrate seizures after inadvertent intraventricular administration.^34,129,252 Management of cephalosporin overdose is similar to that of penicillin overdose. Table 57–1 lists the pharmacologic mechanism of cephalosporins.

Adverse Effects Associated with Therapeutic Use.

Cephalosporins rarely cause an immune-mediated acute hemolytic crisis.⁷⁰ Cefaclor is the cephalosporin most commonly reported to cause systemic immune complex hypersensitivity or serum sickness, although this can occur with other cephalosporins.^119,140 Also like penicillins, first-generation cephalosporins are associated with chronic toxicity, including interstitial nephritis and hepatitis.²⁴⁹ Cefepime is reported to cause reversible coma and seizures.^1,218

Cross-Hypersensitivity.

The cephalosporins contain a six-member dihydrithiazine ring instead of the five-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. 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 due to a dissimilar antigenic side chain.⁴³ In fact, IgE directed against a methylene substituent linking the side chain to the penicillin molecule is identified.⁹⁵ 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.

Cephalosporins containing an N-methylthiotetrazole (nMTT) side chain (moxalactam, cefazolin, cefoperazone, cefmetazole, cefamandole, cefotetan) have toxic effects unique to their group structure. As these cephalosporins undergo metabolism, they release free nMTT, which is responsible for their effects (Fig. 57–2).¹⁴⁸ Free nMTT inhibits the enzyme aldehyde dehydrogenase and, in conjunction with ethanol, can cause a disulfiramlike reaction (Chaps. 79 and 80).³⁸

The nMTT side chain is also associated with hypoprothrombinemia, although a causal relationship is controversial.⁹¹ It is thought that nMTT depletes vitamin K-dependent clotting factors by inhibition of vitamin K epoxide reductase.¹⁶⁷ 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.²² Treatment of patients suspected of hypoprothrombinemia caused by these cephalosporins consists of fresh frozen plasma, if bleeding is evident, and vitamin K₁ in doses required to resynthesize vitamin K cofactors (Chap. 60 and Antidotes in Depth: A15).

Other β-Lactam Antimicrobials

Included in this group are monobactams such as aztreonam and carbapenems such as imipenem and meropenem. Table 57–1 lists the pharmacologic mechanism of these xenobiotics.

Effects occurring after acute overdose of other β-lactam antimicrobials resemble those occurring after penicillin exposure. Imipenem has epileptogenic potential in both overdose and therapeutic dosing (see Adverse Effects Associated With Therapeutic Use).^42,131 Management guidelines for other β-lactam overdoses are similar to those for penicillin overdoses.

Adverse Effects Associated with Therapeutic Use.

The risk factors for imipenem-related seizures include central nervous system disease, prior seizure disorders, and abnormal kidney function.¹⁷³ The mechanism for ­seizures appears to be GABA antagonism (similar to the penicillins) in conjunction with enhanced activity of excitatory amino acids.^62,224

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.²⁰² However, aztreonam cross-reacts in vitro with ceftriaxone, thought to be the result of the similarity in their side-chain structure.¹⁷⁵ 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.²⁰¹

Trimethoprim-Sulfamethoxazole

Trimethoprim and sulfamethoxazole work as antibacterials in tandem effectively preventing tetrahydrofolic acid synthesis in bacterial cells. Significant toxicity after acute overdose is not expected; however, a myriad of effects occur after chronic therapeutic use. Hyperkalemia can result due to 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.^68,164 Other effects commonly reported after use of trimethoprim/sulfamethoxazole combinations include cutaneous allergic reactions, hematologic disorders, methemoglobinemia, hypoglycemia, rhabdomyolysis, and psychosis.

Trimethoprim also inhibits the renal tubular secretion of creatinine resulting in an increase in serum creatinine measurement.⁵⁹ This effect is thought to be dose related and ranges from 13% to 35% in patients with CKD. The rise in creatinine is independent of glomerular filtration rate and resolves upon 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. Table 57–1 lists the pharmacologic mechanism of chloramphenicol.

Acute overdose of chloramphenicol commonly causes nausea and vomiting. 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.⁸¹ 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 µg/mL.^81,154,231 Because concentrations are not readily available, all poisoned patients should be closely observed for at least 12 hours after exposure. Orogastric lavage may be useful for recent ingestions when the patient has not vomited, and activated charcoal 1 g/kg should be orally given.

Extracorporeal means of eliminating chloramphenicol are not usually required because of its rapid metabolism. However, both hemodialysis and charcoal hemoperfusion decrease serum chloramphenicol concentrations and may be of benefit in patients with large overdoses, or in patients with severe hepatic or renal dysfunction.^80,150,215 Exchange transfusion also lowers serum chloramphenicol concentrations in neonates.²²³ Surviving patients should be closely monitored for signs of bone marrow suppression, which is usually dose dependent.

Adverse Effects Associated with Therapeutic Use.

Chronic toxicity of chloramphenicol is similar to that which occurs following acute poisoning. The classic description of chronic chloramphenicol toxicity is the “gray baby syndrome.”¹⁵⁴ 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 unconjugated chloramphenicol in the urine.^88,248

There are two types of bone marrow suppression that occur after use of chloramphenicol. The most common type is dose dependent and occurs with high serum concentrations of chloramphenicol.^106,107,208 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.¹⁵⁷ 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. 22).^69,255 The dehydro and nitroso bacterial metabolites of chloramphenicol injure human bone marrow cells through inhibition of myeloid colony growth, inhibition of DNA synthesis, and inhibition of mitochondrial protein synthesis.¹¹⁵

Other adverse effects associated with chloramphenicol include peripheral neuropathy, neurologic abnormalities (eg, confusion, delirium), optic neuritis, nonlymphocytic leukemia, and contact dermatitis.^{52,124,133,180,213}

Fluoroquinolones

The fluoroquinolones are a structurally similar, synthetically derived group of antimicrobials that have diverse antimicrobial activities. They include balofloxacin, ciprofloxacin, clinafloxacin, enoxacin, fleroxacin, gatifloxacin, gemifloxacin, grepafloxacin, levofloxacin, lomefloxacin, moxifloxacin, nadifloxacin, nalidixic acid, norfloxacin, ofloxacin, pefloxacin, rufloxacin, sparfloxacin, temafloxacin, and tosufloxacin. Like other antimicrobials, the fluoroquinolones rarely produce life-threatening effects following acute overdose, and most patients can be safely managed with minimal intervention.¹¹Table 57–1 lists the pharmacologic mechanism of fluoro­quinolones.

Rarely, acute overdose of a fluoroquinolone results in AKI or seizures.¹²⁷ 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.^54,205 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.^104,187 Treatment includes discontinuation of the fluoroquinolone and supportive care. Improvement in kidney function usually occurs within several days.

Seizures are reported with ciprofloxacin and may be a result of the inhibition of GABA or elevation of neuronal glutamate.^2,216,235 Others postulate that seizures result from the ability of fluoroquinolones to bind efficiently to cations, particularly magnesium. This hypothesis is related to the inhibitory role of magnesium at the excitatory NMDA-gated ion channel (Chap. 14).⁶³ Treatment is supportive, using benzodiazepines and, if necessary, barbiturates to increase inhibitory tone.

Adverse Effects Associated with Therapeutic Use.

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

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

Fluoroquinolones cause prolongation of the QT interval, and they may also cause torsade de pointes.¹⁹⁵ 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 prolongation is supportive.

Fluoroquinolones also rarely result in potentially fatal hepatotoxicity.¹³⁶ This adverse effect is 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 effects on developing ­cartilage and bone.¹¹⁸ Damage is more common to fluoroquinolones with fleroxacin, pefloxacin, levofloxacin, and ofloxacin due to a substitution at the R-7 position of the quinolone core structure. There are very limited data regarding damage to articular cartilage as a result of using fluoroquinolones in humans; however, children given ciprofloxacin on a compassionate basis developed complaints of swollen, painful, and stiff joints after 3 weeks of therapy.¹¹⁴ All signs and symptoms abated within 2 weeks of discontinuation of therapy. However, 29 additional children treated with ofloxacin or ciprofloxacin showed no differences with respect to cartilage thickness, cartilage structure, edema, cartilage-bone borderline, or synovial fluid.⁵⁷ Women who received quinolones during pregnancy had larger babies and more caesarean deliveries because of fetal distress than did controls.¹⁹

Fluoroquinolones are implicated as a cause of tendon rupture, which is reported to occur for months to one year after the start of treatment as well as after the discontinuation of therapy.^174,219 The fluoroquinolone should be discontinued in patients, particularly in athletes who complain of symptoms consistent with painful and swollen tendons.

Other adverse effects include acute psychosis, hyperglycemia, hypoglycemia, rash, tinnitus, eosinophilia, serum sickness, and photo­sensitivity .^{39,92,155,172,222}

Macrolides and Ketolides

The macrolide antimicrobials include various forms of erythromycin (base, ethylsuccinate, gluceptate, lactobionate, stearate), azithromycin, clarithromycin, dirithromycin, fidaxomicin, and troleandomycin. Ketolides are similar in pharmacology to macrolides; telithromycin is the only available agent at this time. Table 57–1 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. However, intravenous overdoses can cause dysrhythmias.²²⁸

Intravenous and oral therapeutic use of macrolides cause QT interval prolongation and dysrhythmias. The QT interval prolongation seen occurs due to blockade of delayed rectifier potassium currents (I_Kr; Chaps. 16 and 64).¹⁹⁴ Erythromycin lactobionate causes QT interval prolongation and torsade de pointes after intravenous use.¹⁶⁸ Oral erythromycin is also implicated in causing prolongation of the QT interval and torsade de pointes, especially in patients concurrently taking cytochrome (CYP3A4) inhibitors, in women, and in those with underlying heart disease.^66,94,181 Oral use of azithromycin use is associated with an increased risk of cardiovascular death with several case reports of QT interval prolongation, torsade de pointes, and polymorphic ventricular tachycardia.¹⁸⁰ In children, intravenous overdoses of azithromycin result in similar findings.

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.³⁵

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 the CYP3A4 enzyme system; azithromycin does not inhibit this enzyme.⁵⁶ Erythromycin inhibits cytochrome P450 after metabolism to a nitroso intermediate, which then forms an inactive complex with the iron (II) of cytochrome P450. The appendix to Chap. 13 lists substrates for the CYP3A4 system. Clinically significant interactions occur with erythromycin and warfarin, carbamazepine, or cyclosporine.^40,99,178 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.²⁹ Cases of carbamazepine toxicity are documented when combined with the use of erythromycin.⁹⁹ Erythromycin also inhibits CYP1A2, producing clinically significant interactions with clozapine, theophylline, and warfarin.¹⁹⁰

Macrolides may also interact with the absorption and renal excretion of xenobiotics that are amenable to intestinal P-glycoprotein excretion, or interfere with normal gut flora responsible for metabolism. This may be part of the underlying mechanism of cases of macrolide-induced digoxin toxicity (Chap. 65).¹⁶⁶

End-organ effects.

The most common toxic effect of macrolides after chronic use is hepatitis, which may be immune mediated.⁴⁴ Erythromycin estolate is the macrolide most frequently implicated in causing cholestatic hepatitis.^87,111

Large doses (> 4 g/day) of macrolide antimicrobials are also associated with reversible high-frequency sensorineural hearing loss.³⁶ Renal impairment may be a risk factor.^198,225 There are rare case reports in which ototoxicity did not resolve following discontinuation of therapy.¹³² Other, rare toxic effects associated with macrolides include cataracts after clarithromycin use in animals and acute pancreatitis in humans.^75,239 Allergy is rare and reported at a rate of 0.4% to 3%.⁶⁰ Telithromycin contains a carbamate side chain that may interfere with the normal function of neuronal cholinesterase. It should be used cautiously in patients with myasthenia gravis, particularly patients receiving pyridostigmine because of the risk of cholinergic crisis.²²⁹

Clindamycin is a lincosamide with similar structure and clinical effects to macrolides. Clindamycin phosphate is commonly used topically while clindamycin hydrochloride is available for intravenous use. Data regarding acute overdose are limited and most cases of chronic toxicity occur after use of systemic doses of clindamycin phosphate. The most consequential toxicity is gastrointestinal resulting in esophageal ulcers, diarrhea, and C. difficile mediated enterocolitis.¹⁸⁸

Sulfonamides

Sulfonamides antagonize para-aminobenzoic acid or paraaminobenzyl glutamic acid, which are required for the biosynthesis of folic acid. Table 57–1 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.⁷⁹ Treatment is similar to acute oral penicillin overdoses.

Adverse Effects Associated with Therapeutic Use.

The most common adverse effects associated with sulfonamide therapy are nausea and cutaneous hypersensitivity reactions. Hypersensitivity reactions are thought to be caused by the formation of hapten sulfamethoxazole metabolites, N-hydroxy-sulfamethoxazole and nitroso-sulfamethoxazole. The degree of hapten binding is mitigated in vitro by cysteine and glutathione.¹⁵⁸ 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.¹³⁰ This may be caused by a decrease in the mechanisms available for detoxification of free radical formation, as cysteine and glutathione concentrations are low in these patients.²⁴⁶ Whether supplementation with a glutathione precursor such as N-acetylcysteine will reduce the incidence of these reactions is unknown.⁴

Methemoglobinemia and hemolysis occur rarely.^67,159 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.²⁵⁵ This finding may be of particular importance in treating patients with glucose-6-phosphate dehydrogenase deficiency associated with decreased in reducing capabilities.⁵

The sulfonamides are associated with many chronic adverse effects. Bone marrow suppression is rare, but the incidence is increased in patients with folic acid or vitamin 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 effects include hypersensitivity pneumonitis, stomatitis, aseptic meningitis, hepatotoxicity, renal toxicity, and central nervous system toxicity.²⁵

Tetracyclines

Tetracyclines are derivatives of Streptomyces cultures. Currently available tetracyclines include demeclocycline, doxycycline, methacycline, minocycline, oxytetracycline, and tetracycline. Table 57–1 lists the pharmacologic mechanism of tetracyclines. Significant toxicity after acute overdose of tetracyclines is unlikely. Gastrointestinal effects consisting of nausea, vomiting, and epigastric pain have been reported.³⁷

Adverse Effects 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 pregnancy because of the risk of development of secondary tooth discoloration in children or developing children in utero. Tooth discoloration can be effectively removed using topical application of carbamide peroxide whitening treatments.²³⁴ Other effects associated with tetracyclines include nephrotoxicity, hepatotoxicity, skin hyperpigmentation in sun-exposed areas, and hypersensitivity reactions.^{44,90,109,227} More severe hypersensitivity reactions, 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.^143,207,212 Demeclocycline rarely causes ­nephrogenic diabetes insipidus (Chaps. 19 and 28).⁴⁵

Vancomycin

Vancomycin is obtained from cultures of Nocardia orientalis and is a tricyclic glycopeptide. Vancomycin is biologically active against numerous Gram-positive organisms. Table 57–1 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 due to sustained high serum concentrations. In these patients, multiple doses of activated charcoal and potentially high-flux hemodialysis can be considered to enhance clearance.^125,238

Adverse Effects Associated with Therapeutic Use.

Patients who receive intravenous vancomycin may develop the “red man syndrome” through an anaphylactoid (non–IgE-mediated) mechanism.⁸⁴ Symptoms include chest pain, dyspnea, pruritus, urticaria, flushing, and angioedema.¹⁹³ Signs and symptoms spontaneously resolve, typically within 15 minutes. Other symptoms attributable to “red man syndrome” include hypotension, cardiovascular collapse, and seizures.^13,162

The incidence of red man syndrome appears to be related to the rate of infusion and is approximately 14% when 1 g is given over 10 minutes, and falls dramatically to only 3.4% when given over 1 hour.^162,169 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.^134,200 Tachyphylaxis occurs in patients given multiple doses of vancomycin.^97,245 Animal models demonstrated a direct myocardial depressant and vasodilatory effect of vancomycin.⁵³ More ­serious reactions result when vancomycin is given via intravenous bolus, further supporting a rate-related anaphylactoid mechanism.²¹

Patients most often experience red man syndrome after vancomycin is administered intravenously. In rare cases, oral administration of vancomycin can also result in the syndrome.¹⁸ Treatment includes increasing the dilution of vancomycin and slowing intravenous administration. Antihistamines may be useful as pretreatment, especially prior to the first dose.¹⁸³ A placebo-controlled trial in adult patients studied the incidence of these symptoms in patients given 1 g of vancomycin over one hour, as well as the effect of diphenhydramine in the prevention of the syndrome.²⁴⁵ There was a 47% incidence of reaction without diphenhydramine and a 0% incidence with diphenhydramine.

Chronic use of vancomycin may cause reversible nephrotoxicity, particularly in patients with prolonged excessive steady-state serum concentrations.^10,186 Concomitant administration of aminoglycoside antimicrobials may increase the risk of nephrotoxicity.¹⁹⁶ Vancomycin also causes, though rarely, thrombocytopenia and neutropenia.^50,51,65

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 57–1 lists the pharmacologic mechanism of amphotericin B. Development of lipid and colloidal formulations of amphotericin B attenuate the adverse effects associated with amphotericin B.⁹³ 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.¹⁰¹

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.^31,51,122 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 Effects Associated with Therapeutic Use.

Infusion of amphotericin B results in fever, rigors, headache, nausea, vomiting, hypotension, tachycardia, and dyspnea.¹⁴⁴ Pretreatment with acetaminophen, diphenhydramine, ibuprofen, and hydrocortisone is helpful in alleviating the febrile symptoms, as are slower rates of infusion and lower total daily doses.^86,237 Doses greater than 1 mg/kg/day and rapid administration in less than 1 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 may help to alleviate symptoms.

A total of 80% of patients exposed to amphotericin B will sustain some degree of kidney dysfunction (Chap. 28).⁴¹ Initial distal renal tubule damage causes renal artery vasoconstriction ultimately resulting in azotemia.⁷⁶ Studies in animals show depressed renal blood flow and glomerular filtration rate, and increased renal vascular resistance. It is unclear why this occurs, but at this time, renal nerves, angiotensin II, nitric oxide, and tubuloglomerular feedback are excluded.^197,203 The toxic effects associated with amphotericin B may also be caused by the deoxycholate vehicle.²⁵⁴ After large total doses of amphotericin B, residual decreases in glomerular filtration rate may occur even after discontinuation of therapy. This is hypothesized to be the result of nephrocalcinosis. Potassium and magnesium wasting, proteinuria, decreased renal concentrating ability, renal tubular acidosis, and hematuria can also occur (Chaps. 19 and 28).^14,144 Strategies to reduce renal toxicity after amphotericin B include intravenous saline or magnesium and potassium supplementation.^28,77,100 Liposomal formulations of amphotericin B resulted in fewer patients with breakthrough fungal infections, infusion-related fever, rigors, or nephrotoxicity.²⁴⁷ However, chest pain is uniquely reported after use of the liposomal preparation.¹¹⁶

Other adverse effects 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.^135,142,144

Exchange transfusion may be useful in neonates and infants and should be considered after large intravenous doses. In adults, extracorporeal elimination is not expected to be useful because of the low water solubility and high blood-protein binding of the xenobiotic.

Azole Antifungals: Triazole, Imidazoles, and Thiazoles

Triazole antifungals include fluconazole, fosfluconazole, hexaconazole, itraconazole, posaconazole, terconazole, and voriconazole. Common imidazoles include clotrimazole, econazole, ketoconazole, and miconazole. Abafungin is a thiazole. Triazole antifungals treat an array of fungal pathogens, whereas imidazoles and thiazoles 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.²⁶ Rare case reports implicate voriconazole in the development of toxic epidermal necrolysis.¹⁰⁵ 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 57–4 lists other organ system manifestations associated with antifungal agents and other antimicrobials.

Antiparasitics such as thiabendazole, mebendazole, albendazole, diethylcarbazine, ivermectin, metrifonate, niclosamide, oxamniquine, piperazine, praziquantel, and pyrantel pamoate generally have limited toxicity in the overdose. Common symptoms after therapeutic use are gastrointestinal in nature and include abdominal pain, nausea, vomiting, and diarrhea. A single case of ivermectin associated hepatic failure is reported one month after a single dose.²⁴²

Antiviral

Acyclovir and valacyclovir are generally well tolerated in therapeutic doses and overdoses. In 105 dogs ingesting 40 to 2195 mg/kg, gastrointestinal symptoms were most common, with one dog developing mild creatinine increases.¹⁸⁵ A single case report describes AKI with crystalluria after ingestion of 30 g of valacyclovir.¹⁸⁹ Depressed mental status and nephrotoxicity are also reported after therapeutic use in humans.²⁷

The evaluation and management of patients infected with HIV/AIDS continues to dramatically evolve. Medications used to manage this disorder have increased life expectancy as new, more powerful antivirals and xenobiotic combinations become available. Xenobiotic therapy for HIV commonly consists of a combination of xenobiotics from different classes (nucleoside reverse transcriptase inhibitor {NRTI}, nonnucleoside reverse transcriptase inhibitor, protease inhibitor, integrase inhibitor, fusion inhibitor, and C-C chemokine receptor type 5 {CCR5} antagonist) to utilize the advantages of the unique mechanisms that each xenobiotic offers in inhibiting viral replication and minimizing xenobiotic resistance. Drug and dosage errors, particularly in infants, are of significant concern and have resulted in iatrogenic overdose.^30,49,138 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.²³⁰ A comprehensive review of these medications and currently recommended use patterns, drug interactions, and end-organ toxicities can be found at http://aidsinfo.nih.gov/guidelines. Table 57–5 lists the common antimicrobials used to treat HIV-related opportunistic infections, and Table 57–6 lists common adverse xenobiotic effects and overdose effects, if known, for antimicrobials that are specific in their use for HIV-related infections.

Specific Antiretroviral Classes

Nucleoside Analog Reverse Transcriptase Inhibitors.

The nucleoside analog reverse transcriptase inhibitors inhibit the reverse transcription of viral RNA into proviral DNA. Currently available xenobiotics include abacavir, emtricitabine, didanosine (ddI), lamivudine, stavudine, telbivudine, 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.^47,74,145 Following incorporation of the nucleoside analog into mitochondrial DNA by RNA polymerase, DNA polymerase γ is inhibited. This results in decreased production of mitochondrial DNA electron transport proteins, which ultimately inhibits ­oxidative phosphorylation (Chaps. 13 and 23). 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%.⁷⁴ Resolution of symptoms in survivors occurs in 1 to 24 weeks. Patients with NRTI-associated acidemia may recover more quickly after the use of cofactors such as thiamine, riboflavin, L-carnitine, vitamin C, and antioxidants.^33,61 The indications for the use of these xenobiotics are unclear at this time; however, because of the relative lack of toxicity, they may be considered.

Chronic effects.

Development of acidemia is more commonly associated with therapeutic use of reverse transcriptase inhibitors than with acute overdose. The mechanism is likely identical to that described above. Other common adverse effects are somewhat agent specific and include hematologic toxicity after zidovudine, pancreatitis with didanosine, hypersensitivity after abacavir, and sensory peripheral neuropathy after stavudine and didanosine.^{60,61,89,128,153}

Nonnucleoside Reverse Transcriptase Inhibitors.

The nonnucleoside reverse transcriptase inhibitors bind directly to reverse transcriptase enzymes enabling allosteric inhibition of enzymatic function.²³² Delavirdine (Rescriptor), efavirenz (Sustiva), etravirine (Intelence), nevirapine (Viramune), and rilpivirine (Endurant) comprise the currently available xenobiotics.

There are 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 γ-glutamyl transferase, but no other reported effects.⁷¹ An infant received a 40 times therapeutic dose of nevirapine with mild neutropenia and metabolic acidosis with elevated lactate concentration.³⁰ 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.¹⁶⁰ Treatment should include supportive care 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 (proteinase), which is required for viral replication.⁷⁸ Currently available xenobiotics include atazanavir (Reyataz), darunavir (Prezista), fosamprenavir (Lexiva), indinavir (Crixivan), nelfinavir (Viracept), ritonavir (Norvir), saquinavir mesylate (Invirase), and tipranavir (Aptivus).

Data after protease inhibitor overdose are limited. A review of data submitted to the manufacturer of indinavir found that of 79 reports, the complaints were nausea, vomiting, abdominal pain, and nephrolithiasis.Protease inhibitors as a class commonly result in gastrointestinal symptoms and rash.⁷⁸ Drug interactions can occur due to inhibition of CYP isoenzymes.¹⁷⁰ 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.⁷⁸

Fusion Inhibitors.

This class of xenobiotics interferes with the binding or entry of the HIV virion into the cell.²³ No acute overdose data are available for this class, but after chronic use, hypersensitivity, hepatotoxicity, and infusion reactions seem to be of greatest concern.^16,156,163 The currently available drugs include enfuvirtide (Fuzeon) and maraviroc (Selzentry).

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 xenobiotic is raltegravir (Isentress), although elvitegravir and dolutegravir are in stage 2 and 3 clinical trials, respectively. No information is currently available regarding its toxicity after acute overdose. It appears that these xenobiotics are well tolerated at therapeutic doses with a potential association with myotoxicity.

C-C Chemokine Receptor Type 5 Antagonists.

This class of xenobiotics antagonize the receptor by which HIV enters cells. Maraviroc (Selzentry) is the only C-C chemokine receptor type 5 inhibitor currently available. No information is currently available regarding its toxicity after acute overdose.

• Adverse effects attributable to antimicrobials are largely related to chronic administration, although, rarely, acute toxicity does 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 professional will prevent the majority of acute toxic manifestations following antimicrobial use.

References