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CHAPTER 206: Antimicrobials 1327 controlled clinical studies, can be deemed to be “likely” ( Table 205-4).65 Although not usually of clinical relevance, certain herbals may also interfere with assays for therapeutic drugs.66-68 REFERENCES The complete reference list is available online at www.TintinalliEM.com. Antimicrobials Nicholas J. Connors Wallace A. Carter INTRODUCTION Adverse effects associated with antimicrobials occur primarily in three circumstances: side effects with therapeutic dosing, subacute to chronic effects from sustained therapeutic use, and acute toxicity resulting from excessive dosing. Side effects can be immunologic (allergic) or nonim munologic (pharmacologic or idiosyncratic) in nature. Antibiotics cause more reported allergic reactions than other drugs, possibly due to their high frequency of use often in a repeated and interrupted fashion. Sometimes a diluent or other chemical constituent in the formulation of a drug causes the adverse effect. Most patients who sustain an acute antimicrobial overdose remain asymptomatic, and observation is generally all that is required. Mea surement of drug levels is neither helpful nor readily available to affect management but may be confirmatory. Levels are available for several antibiotics such as chloroquine, isoniazid, and quinine. Ancillary testing should be based on the substance ingested and the clinical condition of the patient, such as methemoglobin concentrations for patients with dapsone or chloroquine toxicity. 1 Some antimicrobials are associated with specific, significant toxicities following an acute ingestion and may require directed therapy (Table 206-1). Consider GI decontamination for patients suspected of ingesting a toxic amount of a potentially dangerous antimicrobial agent. Single-dose activated charcoal without sorbitol given orally or via nasogastric tube is most beneficial within 1 hour of the ingestion. 2,3 Multidose activated charcoal is indicated in symptomatic patients who have ingested dapsone or quinine. 4 Hemodialysis or hemoperfusion is effective at reduc ing concentrations of dapsone, 5,6 chloramphenicol, 7 cefepime, 8,9 and possibly pentamidine.10 Ask women of childbearing age about pregnancy and lactation when prescribing antimicrobials. LactMed is a National Library of Medicine and National Institutes of Health database of drugs that describes maternal and infant levels of drugs and effects on breastfed infants and on lactation. Effective June 30, 2015, the U.S. Food and Drug Admin istration published the Pregnancy and Lactation Labeling Rule, which removed pregnancy letter categories (A, B, C, D, and X) and allows for considerations of risk and benefit when prescribing medication to pregnant and nursing women. Also, see Chapter 99, “Comorbid Disorders in Pregnancy, ” for more detailed discussion of drugs in pregnancy. ANTIBACTERIALS  PENICILLINS, CEPHALOSPORINS, AND OTHER a-LACTAM AGENTS Acute overdoses of penicillins and cephalosporins mainly produce nausea, vomiting, and diarrhea but are rarely life threatening. Large doses of penicillins or cephalosporins may produce seizures through γ-aminobutyric acid inhibition, and seizures are managed by administration of benzodiazepines or barbiturates. 11 Seizures resulting from intrathecal doses of penicillins or cephalosporins may require cerebral spinal fluid exchange for treatment.

Large doses of penicillins or cephalosporins may produce seizures through γ-aminobutyric acid inhibition, and seizures are managed by administration of benzodiazepines or barbiturates. 11 Seizures resulting from intrathecal doses of penicillins or cephalosporins may require cerebral spinal fluid exchange for treatment. 12 Imipenem may cause seizures CHAPTER TABLE 206-1 Select Antimicrobial Toxicities and Their Specific Treatments Drug Acute Toxicity Special Therapy for Symptomatic Overdose Antibacterials Penicillin Seizures (50 million units or more IV) Benzodiazepines Amoxicillin Crystalluria, hematuria, acute renal failure IV fluid Cephalosporins Encephalopathy, seizures Benzodiazepines Chloramphenicol Cardiovascular collapse Hemodialysis Fluoroquinolones Seizures Benzodiazepines Macrolides Prolonged QT interval, torsades de pointes arrhythmia Magnesium sulfate Sulfonamides Methemoglobinemia Methylene blue Vancomycin “Red man syndrome” (anaphylactoid response) Slow or stop infusion, antihistamines Antimalarials Chloroquine Seizures, QRS-complex and QT-interval prolongation, hypotension, hypokalemia Epinephrine, diazepam Quinine (quinidine) Sodium-potassium channel blockade, α-adrenergic antagonism, hypoglycemia, ototoxicity, ophthalmic toxicity Multidose activated charcoal, sodium bicarbonate, dextrose, octreotide Primaquine Methemoglobinemia, hemolysis Methylene blue Antituberculous medications Isoniazid Inhibition of γ-aminobutyric acid synthesis and functional deficiency of pyridoxine, seizures Benzodiazepines, highdose pyridoxine in overdose or at therapeutic doses, and these are treated in the same manner. Agitation, encephalopathy, absence seizures, and noncon vulsive status epilepticus have been reported with cefazolin, ceftazidime, cefuroxime, and cefepime. 9,13,14 Patients most at risk for adverse neurologic effects from β-lactams are those with renal failure, those with underlying CNS abnormalities, and those receiving high-dose therapy. 14,15 Amoxicillin overdose may produce crystal-induced inter stitial nephritis, hematuria, and renal failure; treatment is supportive with IV fluids. 16-19 Amoxicillin-clavulanate can cause rare cases of cholestatic hepatitis (1 to 6 weeks after initiation) and pancreatitis.20 Treat with supportive care and discontinuation of the drug. Penicillins are associated with bone marrow suppression, hemolysis, interstitial nephritis, and vasculitis. Cephalosporins are associated with serum sickness and can cause acute hemolytic crisis. 22 Cephalosporins with the N-methylthiotetrazole side chain, such as cefazolin and cefotetan, can produce a disulfiram-like reaction as the side chain is released. Two unique acute adverse reactions to procaine penicillin G are the Jarisch-Herxheimer reaction and Hoigne’s syndrome. The Jarisch- Herxheimer reaction can begin within a few hours following antibiotic treatment of Lyme disease or early syphilis. This reaction is character ized by headache, fever, myalgias, and rash; is usually limited to 24 hours; and results from antigen released from lysed bacteria. Hoigne’s syndrome begins within minutes after an intramuscular or intravascular injection of procaine penicillin G. This syndrome is characterized by extreme apprehension, fear, hallucinations, illusions, hypertension and tachycardia, and seizures. The cause of this reac tion is unclear, but the effects occur in the absence of other signs of anaphylaxis. 25 Amoxicillin and ceftriaxone have been reported to pro duce a similar reaction. 26  CLINDAMYCIN The lincosamide class includes clindamycin and lincomycin, and its main acute toxicities are nausea, vomiting, and diarrhea. Although all Tintinalli_Sec15_p1187-1332.indd 1327 8/2/19 8:40 PM

of other signs of anaphylaxis. 25 Amoxicillin and ceftriaxone have been reported to pro duce a similar reaction. 26  CLINDAMYCIN The lincosamide class includes clindamycin and lincomycin, and its main acute toxicities are nausea, vomiting, and diarrhea. Although all Tintinalli_Sec15_p1187-1332.indd 1327 8/2/19 8:40 PM 1328 SECTION 15: Toxicology antibiotics have been associated with depletion of normal gut flora that allows for proliferation of Clostridium difficile, clindamycin is among those antibiotics that carry a higher risk for this infection and the potential complications of pseudomembranous colitis and toxic megacolon.27 Clindamycin is also associated with two forms of liver injury: (1) tran sient elevations of serum aminotransferases and (2) acute idiosyncratic liver injury characterized by jaundice, alanine transaminase levels 2 to 12 times over baseline, fever, and rash. This latter form of injury usually shows minimal cell injury on liver biopsy and is not associated with liver failure.  FLUOROQUINOLONES Acute overdose of fluoroquinolones rarely produces life-threatening effects. Seizures are a rare consequence of fluoroquinolone use, pos sibly due to γ-aminobutyric acid inhibition or through sequestration of magnesium. 11 There is also an association with prolongation of the QT interval and subsequent torsades de pointes.29 Fluoroquinolones are associated with acute renal failure, possibly through a hypersensitivity reaction where risk factors include concomitant use of renin-angiotensin– blocking agents. 30 Crystal-induced nephropathy has been reported with therapeutic doses of ciprofloxacin. 31 Caution is advised when these antibiotics are used in children due to potential musculoskeletal abnormalities with developing cartilage and bone, although data sug gest the risk is very low. 32 In adults, tendon rupture has been attributed to fluoroquinolone use, with levofloxacin accounting for more than all others combined. 33 Discontinue the antibiotic in those who complain of painful or swollen tendons. Fluoroquinolones are also associated with dysglycemia, rash, serum sickness, and tinnitus.  LINEZOLID The first member of a new class of antibiotic, synthetic oxazolidinones, linezolid inhibits monoamine oxidase and can lead to serotonin syn drome when used concurrently with other serotonergic medications such as selective serotonin reuptake inhibitors. Chronic therapy longer than 28 days is associated with peripheral neuropathy and optic neuropathy with loss of central vision and loss of color and visual acuity. Lactic acidosis can occur, especially in patients with numerous comorbidities including sepsis and cirrhosis. Linezolid is also associated with anemia, thrombocytopenia and pancytopenia, and cholestatic hepatitis.  MACROLIDES AND KETOLIDES Although the most common adverse reaction to macrolide use is GI distress, QT-interval prolongation with potential for torsades de pointes is the most important. 36,37 The mechanism for this effect is blockade of the delayed rectifier potassium currents and has been noted after use of erythromycin, clarithromycin, telithromycin, and, to a lesser extent, azithromycin. Erythromycin and clarithromycin, but not azithromycin, also inhibit cytochrome P450 3A4, potentially causing drug interactions. Macrolides are also associated with high-frequency sensorineural hear ing loss, cholestatic hepatitis, and rarely pancreatitis.  TRIMETHOPRIM-SULFAMETHOXAZOLE These two antimicrobials work together for their antibiotic effect and are associated with many commonly reported adverse effects. Among them are allergic reactions, hematologic disorders, hypoglycemia, methemoglobinemia, rhabdomyolysis, and psychosis.

hepatitis, and rarely pancreatitis.  TRIMETHOPRIM-SULFAMETHOXAZOLE These two antimicrobials work together for their antibiotic effect and are associated with many commonly reported adverse effects. Among them are allergic reactions, hematologic disorders, hypoglycemia, methemoglobinemia, rhabdomyolysis, and psychosis. Trimethoprimsulfamethoxazole is also associated with idiosyncratic acute liver injury with a clinical pattern suggestive of a drug allergy or hypersensitivity mechanism that is particularly common among human immunodeficiency virus–infected patients.  VANCOMYCIN Red man syndrome is an anaphylactoid response related to the rate of IV vancomycin infusion that can include angioedema, chest pain, dyspnea, flushing, pruritus, and urticaria. Rarely, this syndrome can also cause seizures and cardiovascular collapse. Most symptoms resolve within 15 minutes when the infusion is stopped. Continuing the infusion at a slower rate or with increased dilution can help decrease recurrence. Pretreatment with diphenhydramine is also helpful. ANTIFUNGALS  TRIAZOLES Antifungal agents such as fluconazole, clotrimazole, and miconazole are not expected to produce severe toxicity in acute overdose settings. Uncommon adverse reactions such as hepatotoxicity can occur, rarely leading to liver failure and death. Liver injury is hepatocellular and can be accompanied by eosinophilia, fever, and rash. Recovery begins with stopping the drug and may take as long as 3 to 4 months. These antifungals are also associated with neutropenia and thrombocytopenia, and they inhibit cytochrome P450 3A4, potentiating toxicity from other pharmaceuticals.  AMPHOTERICIN B Amphotericin B is used for progressive, life-threatening fungal infections and is rarely encountered in the ED. Acute overdoses are associ ated with fever, headache, nausea, vomiting, rigors, hypotension and tachycardia, anemia, dysrhythmias, electrolyte wasting, nephrotoxicity, neuropathy, and cardiac arrest. ANTIMALARIALS  ATOVAQUONE-PROGUANIL Atovaquone-proguanil (generic Malarone) is most often associated with GI distress and headache. It is quite well tolerated and is considered safe during pregnancy and breastfeeding.  CHLOROQUINE AND HYDROXYCHLOROQUINE Chloroquine toxicity usually begins within 3 hours of ingestion with nausea, vomiting, and diarrhea.43 Cardiovascular collapse may be precipitous, with QRS-complex prolongation and atrioventricular nodal blockade. Hypotension may be more severe than that seen with quinine overdose and is accompanied by respiratory depression and hypokalemia. 44 Neurologic toxicity may include headache, obtundation, and seizures. Aggressive supportive care is needed. A decreased mortality rate has been demonstrated in chloroquine overdose treated with early intuba tion, gastric lavage, deep sedation with benzodiazepines, and vasoactive pressor support with epinephrine to maintain a systolic blood pressure of 100 mm Hg (13.3 kPa). 45-47  MEFLOQUINE Mefloquine is used for prophylaxis or treatment of drug-resistant malaria and is associated with a variety of complications. In addition to GI distress, mefloquine is a rare cause of cardiac depression and severe CNS events, including seizures, hallucinations, and psychosis. Milder CNS effects, such as headache, insomnia, and vivid dreams, occur in up to 25% of patients. Mefloquine is not recommended as first-line therapy and is contraindicated in patients with seizures or psychiatric disorders.  PRIMAQUINE Primaquine is associated with GI distress and may cause hemolytic anemia and methemoglobinemia, especially in a glucose-6-phosphate dehydrogenase–deficient population. Granulocytosis, granulocytope nia, hypertension, dysrhythmia, and neurologic depression are rare complications associated with overdose.

s.  PRIMAQUINE Primaquine is associated with GI distress and may cause hemolytic anemia and methemoglobinemia, especially in a glucose-6-phosphate dehydrogenase–deficient population. Granulocytosis, granulocytope nia, hypertension, dysrhythmia, and neurologic depression are rare complications associated with overdose. 49,50  QUININE The cardiac toxicity of quinine includes both sodium and potassium channel antagonism, which may result in widened QRS-complex Tintinalli_Sec15_p1187-1332.indd 1328 8/2/19 8:40 PM