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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