STERILE VANCOMYCIN HYDROCHLORIDE, USP POWDER FOR SOLUTION

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Active ingredient:
VANCOMYCIN (VANCOMYCIN HYDROCHLORIDE)
Available from:
PHARMACEUTICAL PARTNERS OF CANADA INC
ATC code:
J01XA01
INN (International Name):
VANCOMYCIN
Dosage:
1G
Pharmaceutical form:
POWDER FOR SOLUTION
Composition:
VANCOMYCIN (VANCOMYCIN HYDROCHLORIDE) 1G
Administration route:
INTRAVENOUS
Units in package:
1GM
Prescription type:
Prescription
Therapeutic area:
GLYCOPEPTIDES
Product summary:
Active ingredient group (AIG) number: 0131315001; AHFS: 08:12.28.16
Authorization status:
APPROVED
Authorization number:
00722146
Authorization date:
2008-02-14

PRODUCT MONOGRAPH

Sterile Vancomycin Hydrochloride, USP

Vancomycin Hydrochloride for Injection, USP

Antibiotic

Pharmaceutical Partners of Canada Inc.

Date of Preparation:

45 Vogell Road, Suite 200

January 17, 2008

Richmond Hill, ON

L4B 3P6

Control No.: 119199

NAME OF DRUG

Sterile Vancomycin Hydrochloride, USP

Vancomycin Hydrochloride for Injection, USP

THERAPEUTIC CLASSIFICATION

ANTIBIOTIC

ACTION

In vitro studies indicate that the bactericidal action of vancomycin hydrochloride against

many gram-positive bacteria results from the inhibition of cell-wall synthesis. There is

also evidence that vancomycin alters the permeability of the cell membrane and

selectively inhibits RNA synthesis.

INDICATIONS AND CLINICAL USES

VANCOMYCIN HYDROCHLORIDE IV may be indicated in the therapy of severe or life-

threatening staphylococcal infections in patients who cannot receive or who have failed

respond

penicillins

cephalosporins

have

infections

with

staphylococci resistant to other antibiotics, including methicillin.

VANCOMYCIN

HYDROCHLORIDE

been

used

successfully

alone

treatment of staphylococcal endocarditis.

VANCOMYCIN HYDROCHLORIDE IV 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 (e.g. E. faecalis), VANCOMYCIN

HYDROCHLORIDE IV has been reported to be effective only in combination with an

aminoglycoside.

VANCOMYCIN

HYDROCHLORIDE

been

reported

effective

treatment of diphtheroid endocarditis. VANCOMYCIN HYDROCHLORIDE IV 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

determine

their

susceptibilities

VANCOMYCIN

HYDROCHLORIDE IV.

effectiveness

been

documented

other

infections

staphylococci,

including

osteomyelitis,

pneumonia,

septicemia,

soft-tissue

infections.

When

staphylococcal infections are localized and purulent, antibiotics are used as adjuncts to

appropriate surgical measures.

Although no controlled clinical efficacy trials have been conducted, VANCOMYCIN

HYDROCHLORIDE IV, has been suggested by the American Heart Association and the

American Dental Association for prophylaxis against bacterial endocarditis in patients

allergic to penicillin who have congenital and/or rheumatic or other acquired valvular

heart disease when they 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).

CONTRAINDICATION

VANCOMYCIN

HYDROCHLORIDE

contraindicated

patients

with

known

hypersensitivity to this antibiotic.

WARNINGS

Rapid

bolus

administration

(e.g.

over

several

minutes)

associated

with

exaggerated hypotension, including shock, and, rarely, cardiac arrest.

When given intravenously, toxic serum levels can occur. Vancomycin is excreted fairly

rapidly

kidney

blood

levels

increase

markedly

with

decreased

renal

clearance.During parenteral therapy, the risk of toxicity appears appreciably increased

high

blood

concentrations

prolonged

treatment.

VANCOMYCIN

HYDROCHLORIDE is poorly absorbed orally. Toxic serum levels are therefore not

attained from oral dosage.

Clinically significant serum concentrations have been reported in some patients who

have

taken

multiple

oral

doses

vancomycin

active

C.

difficile-induced

pseudomembranous colitis; therefore, monitoring of serum concentrations may be

appropriate in these patients.

Ototoxicity has occurred when serum levels exceeded 80

g/mL. Deafness may be

preceded by tinnitus. The elderly are more susceptible to auditory damage. Experience

with other antibiotics suggests that deafness may be progressive despite cessation of

treatment.

Concurrent

sequential

other

neurotoxic

and/or

nephrotoxic

agents,

particularly ethacrynic acid, neuromuscular blocking agents, aminoglycoside antibiotics,

polymixin B, colistin, viomycin, and cisplatin, requires careful monitoring.

If parenteral and oral vancomycin are administered concomitantly an additive effect can

occur. This should be taken into consideration when calculating the total dose. In this

situation serum levels of the antibiotic should be monitored.

PRECAUTIONS

VANCOMYCIN HYDROCHLORIDE IV 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 a prompt cessation of these reactions (See Dosage and

Administration and Adverse Reactions).

Because of its ototoxicity and nephrotoxicity, VANCOMYCIN HYDROCHLORIDE should

be used with care in patients with renal insufficiency. If it is necessary to use

VANCOMYCIN HYDROCHLORIDE parenterally in patients with renal impairment, the

dose and/or dose intervals should be adjusted carefully and blood levels monitored.

VANCOMYCIN HYDROCHLORIDE should be avoided (if possible) in patients with

previous hearing loss. If it is used in such patients, the dose of VANCOMYCIN

HYDROCHLORIDE should be regulated by periodic determination of drug levels in the

blood. Patients with renal insufficiency and individuals over the age of 60 should be

given serial tests of auditory function and of vancomycin blood levels. All patients

receiving the drug should have periodic hematologic studies, urinalyses, and liver and

renal function tests.

The prolonged use of VANCOMYCIN HYDROCHLORIDE may result in overgrowth of

non-susceptible organisms. If new infections due to bacteria or fungi appear during

therapy with this product, appropriate measures should be taken, including withdrawal

of VANCOMYCIN HYDROCHLORIDE. In rare instances, there have been reports of

pseudomembranous

colitis

C.

difficile

developing

patients

receive

intravenous vancomycin.

Since VANCOMYCIN HYDROCHLORIDE IV is irritating to tissue and causes drug

fever, pain and possibly necrosis it should never be injected intramuscularly; it must be

administered intravenously. Pain and thrombophlebitis occur in many patients receiving

VANCOMYCIN HYDROCHLORIDE IV and are occasionally severe. The frequency and

severity of thrombophlebitis can be minimized if the drug is administered in a volume of

at least 200 mL of glucose or saline solution and if the sites of injection are rotated.

There

have

been

reports

that

frequency

infusion-related

events

(including

hypotension, flushing, erythema, urticaria, and pruritus) increases with concomitant

administration of anesthetic agents. Infusion-related events may be minimized by the

administration of VANCOMYCIN HYDROCHLORIDE IV as a 60-minute infusion prior to

anesthetic induction.

The safety and efficacy of VANCOMYCIN HYDROCHLORIDE IV administration by the

intrathecal (intralumbar or intraventricular) route have not been assessed.

Some patients with inflammatory disorders of the intestinal mucosa may have significant

systemic

absorption

oral

vancomycin

and,

therefore,

risk

development of adverse reactions associated with the parenteral administration of

vancomycin. The risk is greater if renal impairment is present. It should be noted that

the total systemic and renal clearances of vancomycin are reduced in the elderly.

When patients with underlying renal dysfunction or those receiving concomitant therapy

with an aminoglycoside are being treated, serial monitoring of renal function should be

performed.

In vitro resistance to Vancomycin has been reported among some enterococcal and

staphylococcal isolates.

Usage in Pregnancy: VANCOMYCIN HYDROCHLORIDE should be given to a

pregnant woman only if clearly needed. In a controlled clinical study, VANCOMYCIN

HYDROCHLORIDE was administered to 10 pregnant women for serious staphylococcal

infections

complicating

intravenous

drug

abuse

evaluate

potential

ototoxic

nephrotoxic effects on the infant. VANCOMYCIN HYDROCHLORIDE levels of 13.2 and

16.6

g/mL were measured in cord blood of two patients. No sensorineural hearing loss

or nephrotoxicity attributable to VANCOMYCIN HYDROCHLORIDE was noted. One

infant whose mother received VANCOMYCIN HYDROCHLORIDE in the third trimester

experienced conductive hearing loss that was not attributed to the administration of

VANCOMYCIN HYDROCHLORIDE. Because the number of patients treated in this

study was limited and VANCOMYCIN HYDROCHLORIDE was administered only in the

second and third trimesters, it is not known whether VANCOMYCIN HYDROCHLORIDE

causes fetal harm.

Nursing Mothers: VANCOMYCIN HYDROCHLORIDE is excreted in human milk.

Caution should be exercised if VANCOMYCIN HYDROCHLORIDE is administered to a

nursing woman. Because of the potential for adverse events, a decision should be

made whether to discontinue nursing or discontinue administration of 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.

Geriatrics: The natural decrease 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.

ADVERSE REACTIONS

Infusion-related

Events:

During

soon

after

rapid

infusion

VANCOMYCIN

HYDROCHLORIDE

patients

develop

anaphylactoid

reactions,

including

hypotension, wheezing, dyspnea, urticaria, or pruritis. 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 VANCOMYCIN HYDROCHLORIDE IV is given by

slow infusion over 60 minutes. In studies in normal volunteers, infusion-related events

did not occur when VANCOMYCIN HYDROCHLORIDE IV was administered at a rate of

10 mg/min or less.

Nephrotoxicity:

Rarely,

renal

failure,

principally

manifested

increased

serum

creatinine

concentrations,

especially

patients

given

large

doses

VANCOMYCIN HYDROCHLORIDE, 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 pre-existing kidney dysfunction. When

VANCOMYCIN

HYDROCHLORIDE

discontinued,

azotemia

resolved

most

patients.

Ototoxicity: A few dozen cases of hearing loss associated with VANCOMYCIN

HYDROCHLORIDE

have

been

reported.

Most

these

patients

kidney

dysfunction, pre-existing hearing loss, or concomitant treatment with an ototoxic drug.

Vertigo, dizziness, and tinnitus have been reported rarely.

Hematopoietic: Reversible neutropenia, usually starting one week or more after onset

of therapy with VANCOMYCIN HYDROCHLORIDE or after a total dose of more than 25

g, has been reported in several dozen patients. Neutropenia appears to be promptly

reversible

when

VANCOMYCIN

HYDROCHLORIDE

discontinued.

Thrombocytopenia has rarely been reported. Although a causal relationship has not

been established, reversible agranulocytosis (granulocyte count less than 500/mm

has been reported rarely.

Phlebitis: Inflammation at the injection site has been reported.

Miscellaneous: Anaphylaxis, drug fever, nausea, chills, eosinophilia, hypotension,

wheezing, dyspnea, urticaria, pruritus flushing of the upper body (“red neck”), pain and

muscle spasm of the chest and back, rashes, including exfoliative dermatitis, Stevens-

Johnson syndrome, linear IgA bullous dermatosis and rare cases of vasculitis have

been associated with the administration of VANCOMYCIN HYDROCHLORIDE.

TREATMENT OF OVERDOSAGE

Other than general supportive treatment, no specific antidote is known. Dialysis does

not remove significant amounts of vancomycin. Hemofiltration and hemoperfusion with

polysulfone resin have been reported to result in increased vancomycin clearance.

In managing overdosage, consider the possibility of multiple drug overdoses, interaction

among drugs, and unusual drug kinetics in your patient.

DOSAGE AND ADMINISTRATION

Dosage

Intravenous:

Adults

The usual intravenous dose is 500 mg every six hours or 1 g every twelve 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.

Adults with Impaired Renal Function:

Dosage adjustment must be made in patients with impaired renal function to avoid toxic

serum levels. Serum levels should be checked regularly, since accumulation in such

patients has been reported to occur over several weeks of treatment.

For most patients with renal impairment or the elderly, the dosage calculation may be

made by using the following nomogram

if the creatinine clearance value is known.

Figure 1:

Nomogram Relating Vancomycin Clearance, Creatinine Clearance

and Vancomycin Dose

Moellering, R.C., et al.: Vancomycin Therapy in Patients with Impaired Renal

Function: A Nomogram for Dosage, Ann. Int. Med., 1981, 94:343.

The nomogram is not valid for functionally anephric patients on dialysis. For such

patients, a loading dose of 15 mg/kg of body weight should be given in order to achieve

therapeutic serum levels promptly, and the dose required to maintain stable levels is 1.9

mg/kg/24 h.

When only serum creatinine is available, the following formula (based on sex, weight,

and age of the patient) may be used to convert this value into estimated creatinine

clearance. The serum creatinine should represent a steady state of renal function.

Males: Weight (kg) x (140 - age)

72 x serum creatinine (mg/dL)

Females: 0.85 x above value

In anuria, a dose of 1 g every 7 to 10 days has been recommended.

Neonates, Infants and Children

The following dosage schedule has been used. Infusions should be over

minutes,

divided

incorporated

child's

24-hour

fluid

requirement.

Infants and Neonates

In both neonates and infants it is suggested that an initial dose of 15 mg/kg be given

followed by 10 mg/kg every 12 hours for neonates in the first week of life and every 8

hours thereafter up to the age of one month. Each dose should be administered over

minutes.

Close

monitoring

serum

concentrations

vancomycin

warranted in these patients.

Children

The usual intravenous dosage of VANCOMYCIN HYDROCHLORIDE is 10 mg/kg per

dose given every 6 hours. The majority of patients with infections caused by organisms

susceptible to the antibiotic show a therapeutic response by 48 to 72 hours. The total

duration of therapy is determined by the type and severity of the infection and the

clinical response of the patient. In staphylococcal endocarditis, therapy for 3 weeks or

longer is recommended.

Administration

Intermittent Intravenous Infusion: The reconstituted solution must be FURTHER

DILUTED with 100-200 mL Normal Saline or 5% Dextrose in Sterile Water for Injection.

This should be infused over a period of at least 60 minutes.

See instructions in the Reconstitution section.

Continuous Intravenous Infusion: Should be used only when intermittent infusion is

not practical.

Note:

Infusion-related

events

related

both

concentration

rate

administration of vancomycin. Concentration of no more than 5 mg/mL and rates of no

more than 10 mg/min are recommended in adults (see 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 risk of infusion-related events.

Infusion related events may occur, however, at any rate or concentration.

Note: VANCOMYCIN HYDROCHLORIDE capsules are formulated in a matrix gel that

prevents administration by a nasogastric tube; if this route of administration is being

considered, the IV dosage form should be used.

PHARMACEUTICAL INFORMATION

Chemistry

Trade Name:

STERILE VANCOMYCIN HYDROCHLORIDE

Proper Name:

Vancomycin hydrochloride

Chemical Name:

)-(3S,6R,7R,22R,23S,26S,36R,38aR)-44-[[2-0-(3-Amino-2,3,

6-trideoxy-3-C-methyl-

-L-lyxo-hexopyranosyl)-

-D-glucopyrano-

syl]oxy]-3-(carbamoylmethyl)-10,19-dichloro-2,3,4,5,6,7,23,24,

25,26,36,37,38,38a-tetradecahydro-7,22,28,30,32-pentahydroxy-6-

[(2R)-4-methyl-2-(methylamino)valeramido]-2,5,24,38,39-pentaoxo-

22H-8,11:18,21-dietheno-23,36-(iminomethano)-13,16:31,35-

dimetheno-1H,16H-[1,6,9]oxadiazacyclohexadecino[4,5-m][10,2,16] -benzoxadiazacyclo

-tetracosine-26, carboxylic acid, monohydrochloride

Structure:

Mol. Formula:

.HCl

Mol. Weight:

1485.68

Description:

Vancomycin hydrochloride, is a chromatographically purified tricyclic

glycopeptide

antibiotic

derived

from

Amycolatopsis

orientalis

(formerly

Nocardia

orientalis). It is an off-white free flowing powder, having essentially no odor. It is

soluble in water and insoluble in organic solvents.

Composition

STERILE VANCOMYCIN HYDROCHLORIDE vials for IV use, contain vancomycin

hydrochloride

(expressed

terms

free

base)

lyophilized

plug.

When

reconstituted in water, it forms a clear, colourless solution with a pH range of 2.5 to 4.5.

RECONSTITUTION

Solution for Reconstitution

Sterile Water for Injection USP

Reconstitute as follows:

Table 1:

Reconstitution Table

Volume

Approximate

to be

Approximate

Average

Added to

Available

Vancomycin

Vial Size

Vial

Volume

Concentration

500 mg

10 mL

10.3 mL

50 mg/mL

1.0 g

20 mL

20.6 mL

50 mg/mL

Shake well until dissolved.

Note:

Further Dilution is Required.

Note: Prior to administration, parenteral drug products should be inspected visually for

particulate matter and discoloration whenever solution or container permits.

For Intermittent Intravenous Infusion

500 mg vial: Reconstituted solutions must be diluted with at least 100 mL of 0.9%

Sodium Chloride Injection or 5% Dextrose in Sterile Water for Injection.

1 g vial: Reconstituted solutions must be diluted with at least 200 mL of 0.9% Sodium

Chloride Injection or 5% Dextrose in Sterile Water for Injection.

For Continuous Intravenous Infusion

The vials reconstituted according to the above table should be further diluted to the

desired volume with any of the solutions for IV infusion listed below.

Solutions for IV Infusion

5% Dextrose Injection

5% Dextrose Injection and 0.9% Sodium Chloride Injection

Lactated Ringer's Injection

Lactated Ringer's in 5% Dextrose Injection

Normosol

-M in D5-W

0.9% Sodium Chloride Injection

Isolyte

Acetated Ringer's Injection

Pharmacy Bulk Vial

AVAILABILITY

BULK

PHARMACY

VIAL

RESTRICTED

HOSPITALS WITH A RECOGNIZED INTRAVENOUS ADMIXTURE PROGRAM.

VANCOMYCIN

HYDROCHLORIDE

INJECTION

does

contain

preservatives.

Pharmacy

Bulk

Vial

intended

multiple

dispensing

intravenous use only, employing a single puncture.

Table 2:

Reconstitution Table

Vial Size

Volume

to be

Added to

Vial

Approximate

Available

Volume

Approximate

Average

Vancomycin

Concentration

10 g

95 mL

100 mL

100 mg/mL

Note:

Reconstitute with Sterile Water for Injection.

Use reconstituted stock solution within 8 hours, and further diluted solutions within 24

hours if kept at room temperature and 96 hours if refrigerated from time of initial

puncture.

STABILITY AND STORAGE RECOMMENDATIONS

Dry Powder

Store between 15 and 25° C.

Solutions

Reconstituted stock solution for Pharmacy Bulk vials should be used within 8 hours. All

other reconstituted solutions and further diluted infusion mixtures should be used within

24 hours if kept at room temperature or 96 hours when refrigerated.

Incompatibility

Vancomycin solution has a low pH that may cause physical or chemical instability when it is

mixed with other compounds. Mixing with alkaline solutions should be avoided.

Mixtures of solutions of vancomycin and beta-lactam antibiotics have been shown to be

physically incompatible. The likelihood of precipitation increases with higher concentrations of

vancomycin.

recommended

adequately

flush

intravenous

lines

between

administration of these antibiotics. It is also recommended to dilute solutions of vancomycin to 5

mg/mL or less.

Although intravitreal injection is not an approved route of administration for vancomycin,

precipitation has been reported after intravitreal injection of vancomycin and ceftazidime for

endophthalmitis using different syringes and needles. The precipitates dissolved gradually, with

complete clearing of the vitreous cavity over two months and with improvement of visual acuity.

Some of the specific substances found incompatible are aminophylline, chloramphenicol

sodium succinate, dexamethasone phosphate, diphenylhydantoin

sodium, methicillin, vitamin B

complex with C, sulfisoxazole diethanolamine, heparin

sodium, potassium penicillin G,

hydrocortisone

sodium

succinate,

amobarbital

sodium,

nitrofurantoin

sodium,

pentobarbital sodium, phenobarbital sodium, secobarbital sodium, sodium bicarbonate,

and sulfadiazine sodium.

Note:

Common flavouring syrups have been added to the solution to improve

the taste for oral administration. There is no information to indicate that

the potency or efficacy of the drug is affected by the addition of these

agents.

AVAILABILITY OF DOSAGE FORMS

STERILE

VANCOMYCIN

HYDROCHLORIDE

available

sterile

lyophilized

powder in vials containing vancomycin hydrochloride equivalent to 500 mg and 1 g

vancomycin base.

VANCOMYCIN HYDROCHLORIDE FOR INJECTION Pharmacy Bulk Vial 7355 is

available in vials containing vancomycin hydrochloride equivalent to 10 g vancomycin

base, edetate calcium disodium equivalent to 0.2 mg edetate/g vancomycin, and

ethanol equivalent to up to 30 mg/g vancomycin.

MICROBIOLOGY

Cross-resistance

been

demonstrated

between

VANCOMYCIN

HYDROCHLORIDE and other classes of antibiotics. Laboratory-induced resistance has

been reported to occur in a slow stepwise fashion. The development of resistance to

vancomycin by staphylococci has not been reported in clinical use. Its activity is not

significantly altered by changes in pH or by the presence of serum. Vancomycin is

active against most strains of the following organisms in vitro and in clinical infections:

Staphylococcus aureus (including heterogeneous methicillin-resistant strains)

Clostridium difficile

S. epidermidis (including heterogeneous methicillin-resistant strains)

Streptococcus pneumoniae (including multiple-resistant strains)

S. pyogenes (group A beta-hemolytic)

S. agalactiae (group B beta-hemolytic)

S. bovis

Alpha-hemolytic streptococci (viridans groups)

Enterococci (e.g., E. faecalis)

Bacillus sp.

Listeria monocytogenes

Lactobacillus sp.

Neisseria sp.

Diphtheroids

Actinomyces sp.

Note:

Many strains of streptococci, staphylococci, C. difficile, and other gram-

positive bacteria are susceptible in vitro to concentrations of 0.5 to 5

g/mL.

Staphylococci are generally susceptible to less than 5

g/mL of vancomycin

hydrochloride, but a small proportion of S. aureus strains requires 10 to

g/mL for inhibition.

In vitro resistance to Vancomycin has been reported among some enterococcal and

staphylococcal isolates.

Vancomycin is not effective in vitro against gram-negative bacilli, mycobacteria, or fungi.

Table 3:

In Vitro Activity of Vancomycin

MIC (

g/mL)

Organism

No. of Strains

Range

Median

Staphylococcus aureus

1.0 - 2.0

0.78 - 12.5

0.25 - 1.0

Staphylococcus aureus

0.5 - 4.0

(methicillin-resistant)

0.3 - 12.0

0.2 - 3.12

Streptococcus epidermidis

1.56 - 6.25

0.4 - 3.1

0.2 - 6.25

3.12

Streptococcus pneumoniae

0.125 - 0.5

0.25

Streptococcus pyogenes

0.8 - 3.1

Streptococcus viridans

0.39 - 1.56

0.78

Streptococcus

group

Enterococci

0.8 -> 100.0

Clostridium perfringens

0.4 - 1.6

Clostridium ramosum

3.1 - 12.5

Clostridium difficile

<1.0

<1.0

1.0 - 4.0

Methods of Susceptibility Testing

When the standardized method of disc susceptibility testing is used, a 30

g disc of

vancomycin

should

produce

zone

more

than

when

contact

with

"susceptible" organisms. A zone size of 10-11 mm indicates intermediate susceptibility,

while a zone size of 9 mm or less indicates resistance.

With the WHO-ICS agar dilution and broth dilution methods, an MIC of < 5

g/mL

indicates susceptibility to vancomycin.

Assay Methods

Vancomycin

serum

tissue

levels

determined

Bennett's

agar-well

diffusion method. This test can quantitatively measure vancomycin concentrations from

0.5 to 8

g/mL.

Two disc-diffusion assay methods are available for vancomycin. Both use Bacillus

subtilis as the test organism. The first method, which uses antibiotic medium No. 5, is

capable of measuring vancomycin levels from approximately 5 to 40

g/mL. The

second uses minimal salt agar and is capable of detecting vancomycin concentrations

from about 0.8 to 25

g/mL. A modification of this assay permits reliable bioassay for

vancomycin (in concentrations of 0.78 to 50.0

g/mL) in the presence of rifampin or

aminoglycosides. Two commercially prepared assay methods are now available and

include

radioimmunoassay

automated

fluorescence

polarization

immunoassay.

PHARMACOLOGY

HUMAN PHARMACOLOGY

Adults:

Intravenous Administration:

Vancomycin is 55% protein bound as measured by ultrafiltration at Vancomycin serum

levels of 10 to 100 mg/L.

About 75% of an administered dose of vancomycin is excreted in urine by glomerular

filtration in the first 24 hours. Mean plasma clearance is about 0.058 L/kg/h, and mean

renal clearance is about 0.048 L/kg/h. Renal Vancomycin clearance is fairly constant

and accounts for 70% to 80% of Vancomycin elimination. When a single intravenous

injection of 500 mg of vancomycin was administered over 30 minutes to healthy

volunteers, the mean serum peak concentration was 51

g/mL, 18.6

g/mL at 1 hour

and 5.8

g/mL at 6 hours post infusion. After a 1 g single dose I.V. over 30 minutes, the

mean peak level was 85

g/mL, 29

g/mL at 1 hour, 11

g/mL at 6 hours, and 5.1

g/mL at 12 hours post infusion. Following multiple dosages of 500 mg every 6 hours

infused over 30 minutes, the mean peak ranged from 41-57

g/mL. Following multiple

60 minute 1 g I.V. infusions of vancomycin in healthy volunteers, mean peak plasma

concentrations were 64

g/mL, 12.5

g/mL at 6 hours, and 7

g/mL at 12 hours post

infusion. The plasma half-life ranged from 3 to 8 hours with an overall mean of 4.5

hours.

There is no apparent metabolism of the drug.

Renal Insufficiency:

Infusions of 1 g vancomycin in 250 mL D5-W were given over 30 minutes to 29 anephric

patients. After 18 days with intermittent dialysis at three-day

intervals, the serum concentration was still 3.5

g/mL. The elimination half-life was

about 7.5 days.

Tissue Penetration and Distribution:

Central Nervous System: Vancomycin does not readily diffuse across normal meninges

into the spinal fluid; but, when the meninges are inflamed, penetration into the spinal

fluid occurs.

Other Tissues and Fluids: Vancomycin concentration in human pericardial, pleural, bile,

ascitic and synovial fluids reaches approximately one third of the equivalent serum level

after single intravenous doses. A level of 7.6

g/mL was achieved in the brain cyst of

one infant following intravenous infusion of 40 mg/kg daily for 4 days.

TOXICOLOGY

Acute Toxicity

Vancomycin was administered to mice, rats and dogs by various routes.

Table 4:

SE (mg/kg) following Vancomycin

Route

Administration

Mouse

Intravenous

Intraperitoneal

2218

1734

Subcutaneous

> 5000

Oral

> 5000

Rats died quickly from CNS-mediated effects, while dogs died, generally from kidney

failure, several days after the intravenous administration.

Vancomycin, when administered intravenously in a 5 percent solution to dogs at a rate

of 0.6 mL/minute, caused a slight dose-related drop in blood pressure. When the same

dogs were given the same doses at a rate of 15 mL/minute, blood pressure dropped

dramatically, as much as 40 percent. Whether the response is due to a direct effect on

histamine receptors or to release of histamine, possibly from mast cells, is not known.

Subchronic Toxicity

Dogs were given daily i.v. doses of vancomycin at 12.5 mg and 50 mg/kg for 21-311

days. Renal damage was seen in 4/22 dogs receiving 50 mg/kg/day.

Monkeys tolerated i.v. doses of 25 and 50 mg/kg/day for 16-187 days, with irritation at

the injection site as the only toxic effect.

Cats received i.v. doses of 25 and 50 mg/kg/day for three months with no systemic

toxicity.

Anaphylaxis could not be induced in 9 guinea pigs that received 100 mg vancomycin

subcutaneously when challenged by a 25 mg i.v. dose, 25 days later.

Intraperitoneal doses of 150 mg vancomycin or 60 mg tobramycin given subcutaneously

to rats, resulted in no nephrotoxicity; however, when administered together, significant

renal toxicity occurred.

Vancomycin 1000 mg/kg administered subcutaneously concurrently with ethacrynic acid

40 mg/kg intravenously, did not produce ototoxicity in a guinea pig model.

Neuromuscular blocking has not been demonstrated in vancomycin-treated rabbits.

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