Otic and Renal Effects
Ototoxicity and nephrotoxicity are the most serious adverse effects of parenteral vancomycin therapy. To date, these adverse effects have not been reported in patients receiving vancomycin orally. The incidences of ototoxicity and nephrotoxicity have not been well established, but clinical experience to date suggests that these adverse effects occur relatively infrequently. Ototoxicity and nephrotoxicity are most likely to occur in patients who have renal impairment, who are receiving IV vancomycin in high doses or for prolonged periods, or who are receiving other ototoxic and/or nephrotoxic drugs. (See Drug Interactions: Ototoxic and Nephrotoxic Drugs.)
Although ototoxicity and nephrotoxicity have been associated with serum or blood vancomycin concentrations of 80-100 mcg/mL, these reactions have occurred with concentrations as low as 25 mcg/mL. Correlations between serum vancomycin concentrations and ototoxicity and nephrotoxicity still remain to be clarified. Vancomycin may cause damage to the auditory branch of the eighth cranial nerve.
Permanent deafness has occurred. Rarely, vertigo, dizziness, and tinnitus have been reported. Tinnitus may precede the onset of deafness and necessitates discontinuance of the drug. Deafness may progress despite cessation of vancomycin therapy. Vancomycin-induced nephrotoxicity may be manifested by transient elevations in BUN or serum creatinine concentrations, and the presence of hyaline and granular casts and albumin in the urine. Fatal uremia has occurred. Rarely, the drug has been associated with acute interstitial nephritis.
Local Effects
Vancomycin hydrochloride is very irritating to tissue and causes necrosis when given IM; therefore, it must be administered IV and care must be taken to avoid extravasation. Pain and thrombophlebitis occur after IV administration in many patients, and occasionally may be severe.
Dermatologic and Sensitivity Reactions
Urticaria, exfoliative dermatitis, macular rashes, eosinophilia, vasculitis, a shock-like state, transient anaphylaxis, and, occasionally, vascular collapse have been reported in patients receiving vancomycin. The drug also has been associated with Stevens-Johnson syndrome in at least one patient. Hypersensitivity reactions reportedly occur in 5-10% of patients receiving vancomycin. Successful desensitization was reported in some patients who had experienced severe systemic allergic reactions to vancomycin but required further therapy with the drug.
Red-man Syndrome
Rapid IV administration of vancomycin has resulted in a hypotensive reaction frequently referred to as the “red-man syndrome” or “red-neck syndrome”. The reaction is characterized by a sudden decrease in blood pressure which can be severe and may be accompanied by flushing and/or a maculopapular or erythematous rash on the face, neck, chest, and upper extremities; the latter manifestations may also occur in the absence of hypotension.
Wheezing, dyspnea, angioedema, urticaria, and pruritus may also occur. Rarely, cardiac arrest or seizures have occurred. Vancomycin-induced hypotension appears to result from a negative inotropic and vasodilating action produced in part by a release of histamine, which is directly related to the rate of infusion; the release of histamine also appears to be responsible for the usual manifestations (e.g., erythema, rash, pruritus) of the “red” characterization.
The reaction usually begins a few minutes after the vancomycin infusion is started, but may not occur until after the infusion is completed, and usually resolves spontaneously over one to several hours after discontinuance of the infusion. If the hypotensive reaction is severe, the use of antihistamines, corticosteroids, or IV fluids may be necessary. The hypotensive reaction is related to the rate of infusion of vancomycin and has been reported most frequently when the drug was administered over a period of 10 minutes or less; however, the reaction may also occur rarely when the drug is infused over a period of 1 hour or longer.
To minimize the risk of a hypotensive reaction, vancomycin should be infused over a period of at least 1 hour and the patient’s blood pressure should be monitored during the infusion. In patients who have had the reaction, subsequent doses of vancomycin can usually be given without adverse effect if administered at a slow rate (e.g., over several hours). Pretreatment with antihistamines may be of benefit.
If attempts to minimize the reaction fail, use of another anti-infective agent may be necessary. The reaction reportedly has occurred in more than 50% of healthy individuals given vancomycin but less frequently when the drug is used therapeutically. In one study, intradermal skin tests with vancomycin were used to assess the possibility of predicting the severity of vancomycin-associated anaphylactoid reactions (i.e., “red-man syndrome” or “red-neck syndrome”).
Although the intradermal tests were positive (wheal and flare) in all patients and all patients subsequently experienced anaphylactoid reactions following an IV dose of the drug, the magnitude of cutaneous response was of little value in predicting the severity of “red-man syndrome”.
Desensitization, employing sequential incremental concentration and dose increases (in a manner typical for drug desensitization procedures) and pretreatment with an antihistamine and corticosteroid, has been performed successfully in a few patients in whom vancomycin therapy was considered necessary. In at least one patient, oral administration of vancomycin resulted in the “red-man syndrome”. This reaction was characterized by intense pruritus on the arms, scalp, and face; flushing on the face and neck; and erythema on the face, neck, chest, and arms. Administration of a parenteral antihistamine provided some relief.
Evidence from at least one patient suggests possible cross-sensitivity between teicoplanin administration and vancomycin-induced red-man syndrome.
Hematologic Effects
Adverse hematologic effects of vancomycin include leukopenia, eosinophilia, and, rarely, thrombocytopenia. Neutropenia, which appears to be rapidly reversible following discontinuance of the drug, has occurred in some patients, usually beginning 7 or more days after initiation of therapy or after a total dose of more than 25 g of the drug. Although a causal relationship to vancomycin has not been established, reversible agranulocytosis (granulocytes <500/mm3) has been reported rarely in patients receiving vancomycin therapy.
GI Effects
Antibiotic-associated pseudomembranous colitis, caused by toxin-producing clostridia (e.g., C. difficile), has been reported with the use of anti-infective agents, including IV vancomycin.
Pseudomembranous colitis may occur during or following discontinuance of anti-infective therapy and ranges in severity from mild to life-threatening. Mild cases of colitis may respond to discontinuance of the drug alone, but diagnosis and management of moderate to severe cases should include appropriate bacteriologic studies and treatment with fluid, electrolyte, and protein supplementation as indicated; rarely, cautious use of sigmoidoscopy (or other appropriate endoscopic examination) may be considered necessary. If colitis is moderate to severe and is not relieved by discontinuance of the drug, appropriate anti-infective therapy (e.g., metronidazole) should be administered. Nausea also has been reported in patients receiving vancomycin therapy.
Other Adverse Effects
A throbbing pain in the muscles of the back and neck has been reported with vancomycin and can usually be minimized or avoided by slower administration of the drug. In patients undergoing continuous ambulatory peritoneal dialysis (CAPD), intraperitoneal administration of vancomycin has been associated with chemical peritonitis, a syndrome consisting of a cloudy dialysate, which may be accompanied by abdominal pain and fever.
Chemical peritonitis usually disappears shortly after discontinuance of intraperitoneal vancomycin. Other adverse effects of vancomycin include chills and fever. Priapism after a second IV dose of vancomycin, with recurrence on inadvertent rechallenge, occurred in a 37-year-old man with severe underlying diabetes mellitus; bilateral phlebotomy of the corpus cavernosum resulted in resolution of the priapism.
Precautions and Contraindications
Because vancomycin is ototoxic and nephrotoxic, the drug should be used with caution in patients with impaired renal function and should be avoided in patients with previous hearing loss. If it is necessary to use vancomycin in such patients, dosage should be reduced.
Patients with borderline renal function and those older than 60 years of age should be given serial tests of auditory function, and serum or blood vancomycin concentrations should be determined regularly during treatment with the drug.
All patients receiving vancomycin should have periodic urinalysis and renal function tests. The manufacturers also recommend periodic monitoring of the leukocyte count in patients receiving prolonged vancomycin therapy and in those receiving concomitant therapy with drugs that may cause neutropenia. The possibility of red-man syndrome, including potentially severe hypotension, should be considered with vancomycin therapy, particularly with rapid IV infusion.
Prolonged use of vancomycin hydrochloride may result in overgrowth of nonsusceptible organisms. The patient should be carefully monitored and appropriate therapy should be instituted if a superinfection occurs. Because antibiotic-associated pseudomembranous colitis has been reported with the use of anti-infective agents, including IV vancomycin, it should be considered in the differential diagnosis of patients who develop diarrhea during therapy with the drug. Vancomycin is contraindicated in patients with known hypersensitivity to the drug.
Pediatric Precautions
Vancomycin should be used with caution in premature neonates and young infants because of the renal immaturity of these patients and the potential for increased serum concentrations of the drug.
Close monitoring of serum vancomycin concentrations may be warranted in neonates and young infants. Concomitant administration of vancomycin and anesthetic agents in children has been associated with erythema and histamine-like flushing.
The occurrence of infusion-related adverse effects may be minimized by infusing vancomycin over a period of at least 1 hour prior to induction of anesthesia. Safety of the chemical components that may leach out of the plastic container for commercially available frozen vancomycin injections has not been established in children.
Geriatric Precautions
Because geriatric adults may have decreasing glomerular filtration with increasing age, increased serum vancomycin concentrations may occur if dosage is not adjusted in these patients. Vancomycin dosage in geriatric patients should be adjusted based on the degree of renal impairment. (See Dosage: Dosage in Renal Impairment.)
Pregnancy and Lactation
Pregnancy
There was no evidence of teratogenicity when vancomycin was administered IV to rats in dosages up to 200 mg/kg daily (1180 mg/m2 or equivalent to the recommended maximum human dosage based on mg/m2) or to rabbits in dosage up to 120 mg/kg daily (1320 mg/m2 or 1.1 times the recommended maximum human dosage based on mg/m2). There were no effects on fetal weight or development in rats at the highest dosage tested or in rabbits given 80 mg/kg daily (880 mg/m2 or 0.74 times the maximum recommended human dosage based on mg/m2).
In one study, no sensorineural hearing loss or nephrotoxicity was reported in neonates born to women who received IV vancomycin for severe staphylococcal infections associated with IV drug abuse during pregnancy. In one infant whose mother received IV vancomycin in the third trimester of pregnancy, conductive hearing loss was reported; however, a causal relationship to vancomycin has not been established. Because the number of pregnant women in this study was limited and vancomycin was only administered during the second and third trimester of pregnancy, it is not known whether the drug can cause fetal harm when administered to pregnant women. Vancomycin should be used during pregnancy only when clearly needed.
Lactation
Vancomycin is distributed into milk following IV administration. Systemic absorption of oral vancomycin is very low and it is not known whether the drug distributes into human milk following oral administration. However, IV and oral vancomycin should be used with caution in nursing women. Because of the potential for serious adverse reactions from the drug in nursing infants, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of vancomycin to the woman.