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Antibiotic Toxicities

Aminoglycosides

Agents include amikacin, gentamicin, kanamycin, tobramycin, streptomycin

Adverse Effects: Ototoxicity and nephrotoxicity

Ototoxicity is caused by destruction of cochlear hair cells in the organ of Corti, resulting in high-frequency, irreversible hearing loss (amikacin)

Vestibular dysfunction results from damage to vestibular hair cells (gentamicin)

Ototoxicity can occur early in treatment or after cessation of antibiotic

Risk Factors for Ototoxicity

Excessive dose

Preexisting renal disease

Excessive peak serum concentrations

Concurrent use of loop diuretics or vancomycin

Prior exposure to aminoglycosides or loud noise

Old age

Hereditary tendency for auditory or vestibular problems

Nephrotoxicity

Characterized by gradual onset of partial to complete, reversible, non-oliguric renal failure

Elevations of BUN and creatinine, hypertension, excessive urine protein

Risk Factors for Nephrotoxicity

High dose

Prolonged course of therapy

Liver disease

Concurrent use of other nephrotoxic medications

Salt and water depletion

Aminoglycoside Drug Interactions

Nephrotoxicity is associated with co-administration of cephalothin, cyclosporine, amphotericin B, furosemide, ethacrynic acid, methoxyflurane, indomethacin

Aminoglycosides potentiate the respiratory suppression of nondepolarizing neuromuscular agents

Oral kanamycin and methotrexate increase methotrexate toxicity

Tetracyclines

Short acting: Oxytetracycline, tetracycline

Intermediate acting: Demeclocycline

Long acting: Doxycycline, minocycline

Tetracyclines

Nausea and vomiting are Photosensitivity

most common Decreased prothrombin activity

Hepatotoxicity occurs following Overgrowth of resistant

high doses, intravenous bacterial organisms

usage, or in pregnancy Esophageal ulcers

Nephrotoxicity in pre- Intravenous administration: pain,

existing renal disease phlebitis, tissue injury if

Tetracycline-calcium extravasation occurs

orthophosphate complex

inhibits bone growth

in neonates and produces

teeth staining

Tetracyclines Drug Interactions

Aluminum, calcium, magnesium, and iron can impair absorption

Effectiveness of oral contraceptives are reduced by tetracyclines

Enhanced renal toxicity with methoxyflurane or loop diuretics

Enhance anticoagulant effect with warfarin

Can cause digoxin toxicity

Reduced concentrations of tetracyclines with rifampin or anticonvulsants

Chloramphenicol

Bone marrow suppression

Dose, duration related and reversible (>7days). Associated with an elevated serum iron, low reticulocyte count, and low hemoglobin

Severe, irreversible, idiosyncratic aplastic anemia (occurs anytime during therapy or weeks after)

Mechanism: direct toxicity of nitroso-chloramphenicol on DNA

Rare Adverse Effects-chloramphenicol

Hepatitis

Pseudomembranous colitis

Encephalopathy

Hemolytic anemia in patients with G6PD deficiency

Ototoxicity from topical preparations

Chloramphenicol Drug Interactions

Phenytoin, cyclophosphamide, and warfarin can have elevated levels because of inhibition of hepatic microsomal enzymes by chloramphenicol

Phenobarbital and rifampin can both induce hepatic microsomal enzymes, reducing chloramphenicol levels

Co-administration of chloramphenicol and cimetidine may increase potential for aplastic anemia

Concurrent use of acetaminophen may increase chloramphenicol metabolism

Chloramphenicol

Can cause direct myocardial metabolic derangement (grey baby syndrome), with diminished tissue oxygenation and shock

Abdominal distention, emesis, respiratory failure, cyanosis, hypotension or shock; metabolic acidosis can occur beyond the neonatal period

Usually associated with levels >30-40 mg/L

Rifamycins

Rifampin, rifabutin

Contraindicated in pregnancy

Causes orange discoloration of urine, tears and all biologic secretions in 80% of patients

Rapid and potent inducers of CYP3A4, the most abundant human cytochrome P450, found predominately in the liver and small intestine

Reduced Serum Concentrations

Oral anticoagulants Glucocorticoids

(warfarin) (prednisone)

Benzodiazepines Azole antifungals

(diazepam) (fluconazole)

Cardioactive drugs Immunosuppressives

(digoxin) (cyclosporine)

Contraceptive steroids Anticonvulsants

(norethindrone) (phenytoin)

Hypoglycemic agents Antimycobacterials

Metronidazole

Neurotoxicity (seizures, headaches, encephalopathy) may be caused by large doses

Peripheral neuropathy may result from large doses or prolonged courses

Sulfonamides and Trimethoprim

_ Sulfonamides include sulfadiazine, sulfamethoxazole, sulfasalazine, sulfisoxazole

Sulfonamides

_ Rashes are the most common problem

_ Acute IgE-mediated hypersensitivity reactions and drug-induced lupus