VANCOMYCIN
DESCRIPTION:
Vancocin(R) HCl (Sterile Vancomycin Hydrochloride, USP), IntraVenous, is a
chromatographically purified, tricyclic glycopeptide antibiotic derived from
Amycolatopsis Orientalis (formerly Nocardia Orientalis) and has the chemical
formula C66H75Cl2H9O24.HCl. The molecular weight is 1,486; 500 mg of the base is
equivalent to 0.34 mmol.
ACTIONS/CLINICAL PHARMACOLOGY:
Vancomycin is poorly absorbed after oral administration; it is given
intravenously for therapy of systemic infections. Intramuscular injection is
painful.
In subjects with normal kidney function, multiple intravenous dosing of 1 g of
vancomycin (15 mg/kg) infused over 60 minutes produces mean plasma
concentrations of approximately 63 mcgm/mL immediately after the completion of
infusion, mean plasma concentrations of approximately 23 mcgm/mL 2 hours after
infusion, and mean plasma concentrations of approximately 8 mcgm/mL 11 hours
after the end of the infusion. Multiple dosing of 500 mg infused over 30 minutes
produces mean plasma concentrations of about 49 mcgm/mL at the completion of
infusion, mean plasma concentrations of about 19 mcgm/mL 2 hours after infusion,
and mean plasma concentrations of about 10 mcgm/mL 6 hours after infusion. The
plasma concentrations during multiple dosing are similar to those after a single
dose.
The mean elimination half-life of vancomycin from plasma is 4 to 6 hours in
subjects with normal renal function. In the first 24 hours, about 75% of an
administered dose of vancomycin is excreted in urine by glomerular filtration.
Mean plasma clearance is about 0.058 L/kg/h, and mean renal clearance is about
0.048 L/kg/h. Renal dysfunction slows excretion of vancomycin. In anephric
patients, the average half-life of elimination is 7.5 days. The distribution
coefficient is from 0.3 to 0.43 L/kg. There is no apparent metabolism of the
drug. About 60% of an intraperitoneal dose of vancomycin administered during
peritoneal dialysis is absorbed systemically in 6 hours. Serum concentrations of
about 10 mcgm/mL are achieved by intraperitoneal injection of 30 mg/kg of
vancomycin. Although vancomycin is not effectively removed by either
hemodialysis or peritoneal dialysis, there have been reports of increased
vancomycin clearance with hemoperfusion and hemofiltration.
Total systemic and renal clearance of vancomycin may be reduced in the elderly.
Vancomycin is approximately 55% serum protein bound as measured by
ultrafiltration at vancomycin serum concentrations of 10 to 100 mcgm/mL. After
IV administration of Vancocin HCl, inhibitory concentrations are present in
pleural, pericardial, ascitic, and synovial fluids; in urine; in peritoneal
dialysis fluid; and in atrial appendage tissue. Vancocin HCl does not readily
diffuse across normal meninges into the spinal fluid; but, when the meninges are
inflamed, penetration into the spinal fluid occurs.
Microbiology--The bactericidal action of vancomycin results primarily from
inhibition of cell-wall biosynthesis. In addition, vancomycin alters bacterial-
cell-membrane permeability and RNA synthesis. There is no cross-resistance
between vancomycin and other antibiotics. Vancomycin is active against
staphylococci, including Staphylococcus Aureus and Staphylococcus Epidermidis
(including heterogeneous methicillin-resistant strains); streptococci, including
Streptococcus Pyogenes, Streptococcus Pneumoniae (including penicillin-
resistant strains), Streptococcus Agalactiae, the viridans group, Streptococcus
Bovis, and enterococci (eg, Enterococcus Faecalis (formerly Streptococcus
Faecalis)); Clostridium Difficile (eg, toxigenic strains implicated in
pseudomembranous enterocolitis); and diphtheroids. Other organisms that are
susceptible to vancomycin in vitro include Listeria Monocytogenes, Lactobacillus
species, Actinomyces species, Clostridium species, and Bacillus species.
Vancomycin is not active in vitro against gram- negative bacilli, mycobacteria,
or fungi.
Synergy--The combination of vancomycin and an aminoglycoside acts
synergistically in vitro against many strains of S. Aureus, nonenterococcal
group D streptococci, enterococci, and Streptococcus species (viridans group).
Disk Susceptibility Tests--The standardized disk method described by the
National Committee for Clinical Laboratory Standards has been recommended to
test susceptibility to vancomycin. Results of standard susceptibility tests with
a 30-mcgm vancomycin hydrochloride disk should be interpreted according to the
following criteria: Susceptible organisms produce zones greater than or equal to
12 mm, indicating that the test organism is likely to respond to therapy.
Organisms that produce zones of 10 or 11 mm are considered to be of intermediate
susceptibility. Organisms in this category are likely to respond if the
infection is confined to tissues or fluids in which high antibiotic
concentrations are attained. Resistant organisms produce zones of 9 mm or less,
indicating that other therapy should be selected.
Using a standardized dilution method, a bacterial isolate may be considered
susceptible if the MIC value for vancomycin is 4 mcgm/mL or less. Organisms are
considered resistant to vancomycin if the MIC is greater than or equal to 16
mcgm/mL. Organisms having an MIC value of less than 16 mcgm/mL but greater than
4 mcgm/mL are considered to be of intermediate susceptibility. (REF. 1-3)
Standardized procedures require the use of laboratory control organisms. The 30-
mcgm vancomycin disk should give zone diameters between 15 and 19 mm for S.
Aureus ATCC 25923. As with the standard diffusion methods, dilution procedures
require the use of laboratory control organisms. Standard vancomycin powder
should give MIC values in the range of 0.5 mcgm/mL to 2.0 mcgm/mL for S. Aureus
ATCC 29213. For E. Faecalis ATCC 29212, the MIC range should be 1.0 to 4.0
mcgm/mL.
INDICATIONS AND USAGE:
Vancocin HCl is indicated for the treatment of serious or severe infections
caused by susceptible strains of methicillin-resistant (beta-lactam-resistant)
staphylococci. It is indicated for penicillin-allergic patients, for patients
who cannot receive or who have failed to respond to other drugs, including the
penicillins or cephalosporins, and for infections caused by vancomycin-
susceptible organisms that are resistant to other antimicrobial drugs. Vancocin
HCl is indicated for initial therapy when methicillin-resistant staphylococci
are suspected, but after susceptibility data are available, therapy should be
adjusted accordingly.
Vancocin HCl is effective in the treatment of staphylococcal endocarditis. Its
effectiveness has been documented in other infections due to staphylococci,
including septicemia, bone infections, lower respiratory tract infections, and
skin and skin structure infections. When staphylococcal infections are localized
and purulent, antibiotics are used as adjuncts to appropriate surgical measures.
Vancocin HCl has been reported to be effective alone or in combination with an
aminoglycoside for endocarditis caused by Streptococcus Viridans or S. Bovis.
For endocarditis caused by enterococci (eg, E. Faecalis), Vancocin HCl has been
reported to be effective only in combination with an aminoglycoside.
Vancocin HCl has been reported to be effective for the treatment of diphtheroid
endocarditis. Vancocin HCl has been used successfully in combination with either
rifampin, an aminoglycoside, or both in early-onset prosthetic valve
endocarditis caused by S. Epidermidis or diphtheroids.
Specimens for bacteriologic cultures should be obtained in order to isolate and
identify causative organisms and to determine their susceptibilities to Vancocin
HCl.
The parenteral form of Vancocin HCl may be administered orally for treatment of
antibiotic- associated pseudomembranous colitis caused by C. Difficile and for
staphylococcal enterocolitis. Parenteral administration of Vancocin HCl alone is
of unproven benefit for these indications. VANCOCIN HCL IS NOT EFFECTIVE BY THE
ORAL ROUTE FOR OTHER TYPES OF INFECTION.
Although no controlled clinical efficacy studies have been conducted,
intravenous vancomycin has been suggested by the American Heart Association and
the American Dental Association as prophylaxis against bacterial endocarditis in
penicillin-allergic patients who have congenital heart disease or rheumatic or
other acquired valvular heart disease when these patients undergo dental
procedures or surgical procedures of the upper respiratory tract.
Note: When selecting antibiotics for the prevention of bacterial endocarditis,
the physician or dentist should read the full joint statement of the American
Heart Association and the American Dental Association. (REF. 4)
CONTRAINDICATIONS:
Vancocin HCl is contraindicated in patients with known hypersensitivity to this
antibiotic.
WARNINGS:
Rapid bolus administration (eg, over several minutes) may be associated with
exaggerated hypotension, and, rarely, cardiac arrest.
Vancocin HCl should be administered in a dilute solution over a period of not
less than 60 minutes to avoid rapid-infusion-related reactions. Stopping the
infusion usually results in prompt cessation of these reactions.
Ototoxicity has occurred in patients receiving Vancocin HCl. It may be transient
or permanent. It has been reported mostly in patients who have been given
excessive doses, who have an underlying hearing loss, or who are receiving
concomitant therapy with another ototoxic agent, such as an aminoglycoside.
Vancomycin should be used with caution in patients with renal insufficiency
because the risk of toxicity is appreciably increased by high, prolonged blood
concentrations.
Dosage of Vancocin HCl must be adjusted for patients with renal dysfunction (See
Precautions And Dosage and Administration).
PSEUDOMEMBRANOUS COLITIS HAS BEEN REPORTED WITH NEARLY ALL ANTIBACTERIAL AGENTS,
INCLUDING VANCOMYCIN, AND MAY RANGE IN SEVERITY FROM MILD TO LIFE-THREATENING.
THEREFORE, IT IS IMPORTANT TO CONSIDER THIS DIAGNOSIS IN PATIENTS WHO PRESENT
WITH DIARRHEA SUBSEQUENT TO THE ADMINISTRATION OF ANTIBACTERIAL AGENTS.
Treatment with antibacterial agents alters the normal flora of the colon and may
permit overgrowth of clostridia. Studies indicate that a toxin produced by
Clostridium Difficile is a primary cause of "antibiotic-associated colitis."
After the diagnosis of pseudomembranous colitis has been established,
therapeutic measures should be initiated. Mild cases of pseudomembranous colitis
usually respond to drug discontinuation alone. In moderate to severe cases,
consideration should be given to management with fluids and electrolytes,
protein supplementation, and treatment with an antibacterial drug clinically
effective against C. Difficile colitis.
PRECAUTIONS:
General--Clinically significant serum concentrations have been reported in some
patients who have taken multiple oral doses of vancomycin for active C.
Difficile-induced pseudomembranous colitis.
Prolonged use of Vancocin HCl may result in the overgrowth of nonsusceptible
organisms. Careful observation of the patient is essential. If superinfection
occurs during therapy, appropriate measures should be taken.
In order to minimize the risk of nephrotoxicity when treating patients with
underlying renal dysfunction or patients receiving concomitant therapy with an
aminoglycoside, serial monitoring of renal function should be performed and
particular care should be taken in following appropriate dosing schedules (See
Dosage and Administration).
Serial tests of auditory function may be helpful in order to minimize the risk
of ototoxicity.
Reversible neutropenia has been reported in patients receiving Vancocin HCl (See
Adverse Reactions). Patients who will undergo prolonged therapy with Vancocin
HCl or those who are receiving concomitant drugs that may cause neutropenia
should have periodic monitoring of the leukocyte count.
Vancocin HCl is irritating to tissue and must be given by a secure intravenous
route of administration. Pain, tenderness, and necrosis occur with intramuscular
injection of Vancocin HCl or with inadvertent extravasation. Thrombophlebitis
may occur, the frequency and severity of which can be minimized by administering
the drug slowly as a dilute solution (2.5 to 5 g/L) and by rotating the sites of
infusion.
There have been reports that the frequency of infusion-related events (including
hypotension, flushing, erythema, urticaria, and pruritus) increases with the
concomitant administration of anesthetic agents. Infusion-related events may be
minimized by the administration of Vancocin HCl as a 60-minute infusion prior to
anesthetic induction.
The safety and efficacy of vancomycin administration by the intrathecal
(intralumbar or intraventricular) routes have not been assessed.
Reports have revealed that administration of sterile vancomycin HCL by the
intraperitoneal route during continuos ambulatory peritoneal dialysis (CAPD) has
resulted in a syndrome of chemical peritonitis. To date, this syndrome has
ranged from a cloudy dialysate alone to a cloudy dialysate accompanied by
variable degrees of abdominal pain and fever. This syndrome appears to be short-
lived after discontinuation of intraperitoneal vancomycin.
Drug Interactions--Concomitant administration of vancomycin and anesthetic
agents has been associated with erythema and histamine-like flushing (See Usage
in Pediatrics Under Precautions) and anaphylactoid reactions (See Adverse
Reactions).
Concurrent and/or sequential systemic or topical use of other potentially
neurotoxic and/or nephrotoxic drugs, such as amphotericin B, aminoglycosides,
bacitracin, polymyxin B, colistin, viomycin, or cisplatin, when indicated,
requires careful monitoring.
Usage In Pregnancy--Pregnancy Category C--Animal reproduction studies have not
been conducted with Vancocin HCl. It is not known whether Vancocin HCl can
affect reproduction capacity. In a controlled clinical study, the potential
ototoxic and nephrotoxic effects of Vancocin HCl on infants were evaluated when
the drug was administered to pregnant women for serious staphylococcal
infections complicating intravenous drug abuse. Vancocin HCl was found in cord
blood. No sensorineural hearing loss or nephrotoxicity attributable to Vancocin
HCl was noted. One infant whose mother received Vancocin HCl in the third
trimester experienced conductive hearing loss that was not attributed to the
administration of Vancocin HCl. Because the number of patients treated in this
study was limited and Vancocin HCl was administered only in the second and third
trimesters, it is not known whether Vancocin HCl causes fetal harm. Vancocin HCl
should be given to a pregnant woman only if clearly needed.
Nursing Mothers--Vancocin HCl is excreted in human milk. Caution should be
exercised when Vancocin HCl is administered to a nursing woman. Because of the
potential for adverse events, a decision should be made whether to discontinue
nursing or to discontinue the drug, taking into account the importance of the
drug to the mother.
Usage In Pediatrics--In premature neonates and young infants, it may be
appropriate to confirm desired vancomycin serum concentrations. Concomitant
administration of vancomycin and anesthetic agents has been associated with
erythema and histamine-like flushing in children (See Adverse Reactions).
Geriatrics--The natural decrement of glomerular filtration with increasing age
may lead to elevated vancomycin serum concentrations if dosage is not adjusted.
Vancomycin dosage schedules should be adjusted in elderly patients (See Dosage
and Administration).
DRUG INTERACTIONS:
Concomitant administration of vancomycin and anesthetic agents has been
associated with erythema and histamine-like flushing. (See Usage in Pediatrics
Under Precautions) and anaphylactoid reactions (See Adverse Reactions).
Concurrent and/or sequential systemic or topical use of other potentially
neurotoxic and/or nephrotoxic drugs, such as amphotericin B, aminoglycosides,
bacitracin, polymyxin B, colistin, viomycin, or cisplatin, when indicated,
requires careful monitoring.
(See Also PRECAUTIONS.)
ADVERSE REACTIONS:
Infusion-Related Events--During or soon after rapid infusion of Vancocin HCl
patients may develop anaphylactoid reactions, including hypotension (See Animal
Pharmacology), wheezing, dyspnea, urticaria, or pruritus. Rapid infusion may
also cause flushing of the upper body ("red neck") or pain and muscle spasm of
the chest and back. These reactions usually resolve within 20 minutes but may
persist for several hours. Such events are infrequent if Vancocin HCl is given
by a slow infusion over 60 minutes. In studies of normal volunteers, infusion-
related events did not occur when Vancocin HCl was administered at a rate of 10
mg/min or less.
Nephrotoxicity--Rarely, renal failure, principally manifested by increased serum
creatinine or BUN concentrations, especially in patients given large doses of
Vancocin HCl, has been reported. Rare cases of interstitial nephritis have been
reported. Most of these have occurred in patients who were given aminoglycosides
concomitantly or who had preexisting kidney dysfunction. When Vancocin HCl was
discontinued, azotemia resolved in most patients.
Gastrointestinal--Onset of pseudomembranous colitis symptoms may occur during or
after antibiotic treatment (See Warnings).
Ototoxicity--A few dozen cases of hearing loss associated with Vancocin HCl have
been reported. Most of these patients had kidney dysfunction or a preexisting
hearing loss or were receiving concomitant treatment with an ototoxic drug.
Vertigo, dizziness, and tinnitus have been reported rarely.
Hematopoietic--Reversible neutropenia, usually starting 1 week or more after
onset of therapy with Vancocin HCl or after a total dosage of more than 25 g,
has been reported for several dozen patients. Neutropenia appears to be promptly
reversible when Vancocin HCl is discontinued. Thrombocytopenia has rarely been
reported.
Although a causal relationship has not been established, reversible
agranulocytosis (granulocytes <500/mm(cubed)) has been reported rarely.
Phlebitis--Inflammation at the injection site has been reported.
Miscellaneous--Infrequently, patients have been reported to have had
anaphylaxis, drug fever, nausea, chills, eosinophilia, rashes (including
exfoliative dermatitis), Stevens-Johnson syndrome, toxic epidermal necrolysis,
and rare cases of vasculitis in association with administration of Vancocin HCl.
Chemical peritonitis has been reported following intraperitoneal administration
of vancomycin (See Precautions).
OVERDOSAGE:
Supportive care is advised, with maintenance of glomerular filtration.
Vancomycin is poorly removed by dialysis. Hemofiltration and hemoperfusion with
polysulfone resin have been reported to result in increased vancomycin
clearance. The median lethal intravenous dose is 319 mg/kg in rats and 400 mg/kg
in mice.
To obtain up-to-date information about the treatment of overdose, a good
resource is your certified Regional Poison Control Center. Telephone numbers of
certified poison control centers are listed in the Physicians' Desk Reference
(PDR). In managing overdosage, consider the possibility of multiple drug
overdoses, interaction among drugs, and unusual drug kinetics in your patient.
DOSAGE AND ADMINISTRATION:
Sterile vancomycin hydrochloride is intended for intravenous use only. Sterile
vancomycin is Not to be administered orally. Infusion-related events are related
to both concentration and rate of administration of vancomycon. Concentrations
of no more than 5 mg/mL and rates of no more than 10 mg/min are recommended in
adults (see also age-specific recommendations). In selected patients in need of
fluid restriction, a concentration up to 10 mg/mL may be used; use of such
higher concentrations may increase the risk of infusion-related events.
Infusion-related events may occur, however, at any rate or concentration.
Patients With Normal Renal Function
Adults--The usual daily intravenous dose is 2 g divided either as 500 mg every 6
hours or 1 g every 12 hours. Each dose should be administered at no more than 10
mg/min or over a period of at least 60 minutes, whichever is longer. Other
patient factors, such as age or obesity, may call for modification of the usual
intravenous daily dose.
Pediatric Patients--The usual intravenous dosage of Vancocin HCl is 10 mg/kg per
dose given every 6 hours. Each dose should be administered over a period of at
least 60 minutes.
Infants And Neonates--In neonates and young infants, the total daily intravenous
dosage may be lower. In both neonates and infants, an initial dose of 15 mg/kg
is suggested, followed by 10 mg/kg every 12 hours for neonates in the 1st week
of life and every 8 hours thereafter up to the age of 1 month. Each dose should
be administered over 60 minutes. Close monitoring of serum concentrations of
vancomycin may be warranted in these patients.
Patients With Impaired Renal Function And Elderly Patients
Dosage adjustment must be made in patients with impaired renal function. In
premature infants and the elderly, greater dosage reductions than expected may
be necessary because of decreased renal function. Measurement of vancomycin
serum concentrations can be helpful in optimizing therapy, especially in
seriously ill patients with changing renal function. Vancomycin serum
concentrations can be determined by use of microbiologic assay,
radioimmunoassay, fluorescence polarization immunoassay, fluorescence
immunoassay, or high-pressure liquid chromatography.
If creatinine clearance can be measured or estimated accurately, the dosage for
most patients with renal impairment can be calculated using the following table.
The dosage of Vancocin HCl per day in mg is about 15 times the glomerular
filtration rate in mL/min:
DOSAGE TABLE FOR VANCOMYCIN
IN PATIENTS WITH IMPAIRED RENAL FUNCTION
(Adapted from Moellering et al) (REF. 5)
Creatinine Clearance Vancomycin Dose
mL/min mg/24 h
100 1,545
90 1,390
80 1,235
70 1,080
60 925
50 770
40 620
30 465
20 310
10 155
The initial dose should be no less than 15 mg/kg, even in patients with
mild to moderate renal insufficiency.
The table is not valid for functionally anephric patients. For such patients, an
initial dose of 15 mg/kg of body weight should be given to achieve prompt
therapeutic serum concentrations. The dose required to maintain stable
concentrations is 1.9 mg/kg/24 h. In patients with marked renal impairment, it
may be more convenient to give maintenance doses of 250 to 1,000 mg once every
several days rather than administering the drug on a daily basis. In anuria, a
dose of 1,000 mg every 7 to 10 days has been recommended.
When only the serum creatinine concentration is known, the following formula
(based on sex, weight, and age of the patient) may be used to calculate
creatinine clearance. Calculated creatinine clearances (mL/min) are only
estimates. The creatinine clearance should be measured promptly.
Weight (kg) X (140 - age in years)
Men: ------------------------------------------
72 X serum creatinine concentration (mg/dL)
Women: 0.85 X above value
The serum creatinine must represent a steady state of renal function. Otherwise,
the estimated value for creatinine clearance is not valid. Such a calculated
clearance is an overestimate of actual clearance in patients with conditions:
(1) characterized by decreasing renal function, such as shock, severe heart
failure, or oliguria; (2) in which a normal relationship between muscle mass and
total body weight is not present, such as obese patients or those with liver
disease, edema, or ascites; and (3) accompanied by debilitation, malnutrition,
or inactivity.
The safety and efficacy of vancomycin administration by the intrathecal
(intralumbar or intraventricular) routes have not been assessed.
Intermittent infusion is the recommended method of administration.
PREPARATION AND STABILITY
At the time of use, reconstitute by adding either 10 mL of Sterile Water for
Injection to the 500-mg vial or 20 mL of Sterile Water for Injection to the 1-g
vial of dry, sterile vancomycin powder. Vials reconstituted in this manner will
give a solution of 50 mg/mL. FURTHER DILUTION IS REQUIRED.
After reconstitution, the vials may be stored in a refrigerator for 14 days
without significant loss of potency. Reconstituted solutions containing 500 mg
of vancomycin must be diluted with at least 100 mL of diluent. Reconstituted
solutions containing 1 g of vancomycin must be diluted with at least 200 mL of
diluent. The desired dose, diluted in this manner, should be administered by
intermittent intravenous infusion over a period of at least 60 minutes.
Compatibility With Intravenous Fluids--Solutions that are diluted with 5%
Dextrose Injection or 0.9% Sodium Chloride Injection may be stored in a
refrigerator for 14 days without significant loss of potency. Solutions that are
diluted with the following infusion fluids may be stored in a refrigerator for
96 hours:
5% Dextrose Injection and 0.9% Sodium Chloride Injection, USP
Lactated Ringer's Injection, USP
Lactated Ringer's and 5% Dextrose Injection
Normosol(R)-M and 5% Dextrose
Isolyte(R) E
Acetated Ringer's Injection
Vancomycin solution has a low pH and may cause chemical or physical instability
when it is mixed with other compounds.
Prior to administration, parenteral drug products should be inspected visually
for particulate matter and discoloration whenever solution or container permits.
For Oral Administration--Oral Vancocin HCl is used in treating antibiotic-
associated pseudomembranous colitis caused by C. Difficile and for
staphylococcal enterocolitis. Vancocin HCl is not effective by the oral route
for other types of infections. The usual adult total daily dosage is 500 mg to 2
g given in 3 or 4 divided doses for 7 to 10 days. The total daily dosage in
children is 40 mg/kg of body weight in 3 or 4 divided doses for 7 to 10 days.
The total daily dosage should not exceed 2 g. The appropriate dose may be
diluted in 1 oz of water and given to the patient to drink. Common flavoring
syrups may be added to the solution to improve the taste for oral
administration. The diluted solution may be administered via a nasogastric tube.
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