Adverse effects associated with antimicrobials occur primarily in three circumstances: side effects with therapeutic dosing, acute toxicity resulting from excessive dosing, and subacute to chronic effects from sustained therapeutic use. Side effects can be immunologic (allergic) or nonimmunologic (pharmacologic or idiosyncratic) in nature. Antibiotics cause more reported allergic reactions than other drugs, possibly due to their high frequency of use that is 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. Measurement of drug levels is not helpful for 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 particular 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 reducing concentrations of dapsone,^5,6 chloramphenicol, cefepime,^7,8 and possibly pentamidine.⁹

PENICILLINS, CEPHALOSPORINS, AND OTHER β-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. Seizures resulting from intrathecal doses of penicillins or cephalosporins may require cerebral spinal fluid exchange for treatment. Imipenem may cause seizures in overdose or at therapeutic doses, and these are treated in the same manner. Agitation, encephalopathy, absence seizures, and nonconvulsive status epilepticus have been reported with cefazolin, ceftazidime, cefuroxime, and cefepime.^8,10,11 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.^11,12 Amoxicillin overdose may produce crystal-induced interstitial nephritis, hematuria, and renal failure; treatment is supportive with IV fluids.^13,14,15,16

Amoxicillin-clavulanate can cause rare cases of cholestatic hepatitis (1 to 6 weeks following initiation) and pancreatitis.¹⁷ Treat with supportive care and withdrawal of the drug. Penicillins are associated with bone marrow suppression, hemolysis, interstitial nephritis, and vasculitis.¹⁸ Cephalosporins, particularly cefaclor, are associated with serum sickness and can cause acute hemolytic crisis. 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 particular 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 characterized by headache, fever, myalgias, and rash; is usually limited to 24 hours; and results from antigen released from lysed bacteria.¹⁹ 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 reaction is unclear, but the effects occur in the absence of other signs of anaphylaxis. Amoxicillin and ceftriaxone has been reported to produce a similar reaction.

CLINDAMYCIN

The lincosamide class includes clindamycin and lincomycin, and its main acute toxicities are nausea, vomiting, and diarrhea. Although all 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, along with potential complications of pseudomembranous colitis and toxic megacolon.²⁰ Clindamycin is also associated with two forms of liver injury: (1) transient 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.²¹

FLUOROQUINOLONES

Acute overdose of fluoroquinolones rarely produces life-threatening effects. Seizures are a rare consequence of fluoroquinolone use, possibly due to γ-aminobutyric acid inhibition or through sequestration of magnesium, which may also result in prolongation of the QT interval and cause torsades de pointes. Fluoroquinolones are associated with acute renal failure, possibly through a hypersensitivity reaction where risk factors include concomitant use of renin-angiotensin–blocking agents.²² Crystal-induced nephropathy has been reported with therapeutic doses of ciprofloxacin.²³ Caution is advised when using in children due to potential problems with developing cartilage and bone. In adults, tendon rupture has been attributed to fluoroquinolone use for up to 120 days following start of treatment. Discontinue the antibiotic in those who complain of painful or swollen tendons. Fluoroquinolones are also associated with dysglycemia, rash, serum sickness, and tinnitus.¹¹

LINEZOLID

The first member of a new class of antibiotic, synthetic oxazolidinones, linezolid inhibits monoamine oxidase and can lead to serotonin syndrome when used concurrently with other serotonergic medications such as selective serotonin reuptake inhibitors.²⁴

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.²⁵

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.^26,27 The mechanism for this effect is blockade of the delayed rectifier potassium currents and has resulted from use of erythromycin, clarithromycin, telithromycin, and, to a lesser extent, azithromycin. Erythromycin and clarithromycin, but not azithromycin, also inhibit the cytochrome P-450 3A4 enzyme, which can result in severe drug interactions. Additionally, macrolides are associated with high-frequency sensorineural hearing loss, cholestatic hepatitis, and rarely pancreatitis.²⁸

TRIMETHOPRIM-SULFAMETHOXAZOLE