May 30, 2017
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Vancomycin Injection

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Vancomycin Hydrochloride




CLINICAL PHARMACOLOGY

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 mcg/mL immediately after the completion of infusion, mean plasma concentrations of approximately 23 mcg/mL 2 hours after infusion, and mean plasma concentrations of approximately 8 mcg/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 mcg/mL at the completion of infusion, mean plasma concentrations of about 19 mcg/mL 2 hours after infusion, and mean plasma concentrations of about 10 mcg/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 mcg/mL are achieved by intraperitoneal injection of 30 mg/kg of vancomycin. However, the safety and efficacy of the intraperitoneal use of vancomycin has not been established in adequate and well-controlled trials (see PRECAUTIONS).

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 mcg/mL. After IV administration of vancomycin, inhibitory concentrations are present in pleural, pericardial, ascitic, and synovial fluids; in urine; in peritoneal dialysis fluid; and in atrial appendage tissue.

Vancomycin 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 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 Staphylococcus aureus, Streptococcus bovis, enterococci, and the viridans group streptococci.

Vancomycin has been shown to be active against most strains of the following microorganisms, both in vitro and in clinical infections as described in the INDICATIONS AND USAGE section.

Aerobic Gram-Positive Microorganisms

Diphtheroids

Enterococci (e.g., Enterococcus faecalis)
Staphylococci, including Staphylococcus aureus and Staphylococcus epidermidis
(including heterogeneous methicillin-resistant strains)

Streptococcus bovis

Viridans group streptococci

The following in vitro data are available, but their clinical significance is unknown.

Vancomycin exhibits in vitro MIC’s of 1 mcg/mL or less against most (≥90%) strains of streptococci listed below and MIC’s of 4 mcg/mL or less against most (≥90%) strains of other listed microorganisms; however, the safety and effectiveness of vancomycin in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled clinical trials.

Aerobic Gram-Positive Microorganisms

Listeria monocytogenes
Streptococcus pyogenes
Streptococcus pneumoniae
(including penicillin-resistant strains)
Streptococcus agalactiae

Anaerobic Gram-Positive Microorganisms

Actinomyces species
Lactobacillus species

Susceptibility Test Methods

When available, the clinical microbiology laboratory should provide cumulative reports of in vitro susceptibility test results for antimicrobial drugs used in local hospitals and practice areas to the physician as periodic reports that describe the susceptibility profile of nosocomial and community-acquired pathogens. These reports should aid the physician in selecting the most effective antimicrobial.

Dilution Techniques

Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized test method1,2 (broth, agar/or microdilution). The MIC values should be interpreted according to the criteria provided in Table 1.

Diffusion Techniques

Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. The zone size should be determined using a standardized test method2,3. This procedure uses paper disks impregnated with 30 mcg of vancomycin to test the susceptibility of microorganisms to vancomycin. The disk diffusion breakpoints are provided in Table 1.

Table 1: Susceptibility Test Interpretive Criteria for Vancomycin

  Minimum Inhibitory Concentrations (mcg/mL) Disk Diffusion Diameters (mm)
Pathogen Susceptible
(S)
Intermediate
(I)
Resistant
(R)
Susceptible
(S)
Intermediate
(I)
Resistant
(R)
Enterococci ≤4 8 - 16a ≥32 ≥17b 15 – 16b ≤14b
Staphylococcus aureusc,d ≤2 4 - 8 ≥16 - - -
Coagulasenegative staphylococcic,e ≤4 8 - 16 ≥32 - - -
Streptococci spp. other than S. pneumoniae ≤1f,g - - ≥17f,h - -
a Isolates with vancomycin MICs of 8 to 16 mcg/mL should be further screened for vancomycin resistance using standardized procedures.1,2
b Plates should be held for a full 24 hours and examined using transmitted light. Measure the diameter of the zones of complete inhibition (as judged by the unaided eye), including the diameter of the disk. The zone margin should be considered the area showing no obvious, visible growth that can be detected with the unaided eye. Ignore faint growth of tiny colonies that can be detected only with a magnifying lens at the edge of the zone of inhibited growth. Any discernable growth within the zone of inhibition indicates vancomycin resistance. Organisms with intermediate zones should be tested by a standardized dilution method.1,2
c Dilution testing should be performed to determine the susceptibility of all staphylococcal isolates. Disk diffusion testing is not reliable for testing vancomycin, as it does not differentiate vancomycinsusceptible isolates of S. aureus from vancomycin-intermediate isolates, nor does it differentiate among vancomycin-susceptible, intermediate, and resistant isolates of coagulase-negative staphylococci.2
d Any S. aureus isolate for which the vancomycin MIC is ≥ 8 mcg/mL should be sent to a reference laboratory.2
e Any coagulase-negative Staphylococcus isolate for which the vancomycin MIC is ≥ 32 mcg/mL should be sent to a reference laboratory.2
f The rare occurrence of resistant isolates precludes defining any results categories other than “Susceptible”. For isolates yielding results suggestive of a nonsusceptible category, organism identification and vancomycin susceptibility test results should be confirmed. If confirmed, isolates should be sent to a reference laboratory.2
g Interpretative criteria applicable only to tests performed by broth microdilution method using cation-adjusted Mueller-Hinton broth with 2 to 5% lysed horse blood.1,2
h Interpretative criteria applicable only to tests performed by disk diffusion method using Mueller-Hinton agar with 5% defibrinated sheep blood and incubated in 5% CO2. 3

A report of “Susceptible”(S) indicates that the antimicrobial drug is likely to inhibit growth of the pathogen if the antimicrobial drug reaches the concentrations usually achievable at the site of infection. A report of “Intermediate (I) indicates that the result should be considered equivocal, and, if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated.

This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where high dosage of drug can be used. This category also provides a buffer zone which prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of “Resistant”(R) indicates that the antimicrobial drug is not likely to inhibit growth of the pathogen if the antimicrobial drug reaches the concentrations usually achievable at the infection site; other therapy should be selected.

Quality Control

Standardized susceptibility test procedures require the use of laboratory controls to monitor and ensure the accuracy and precision of the supplies and reagents used in the assay, and the techniques of the individuals performing the test. 1, 2, 3 Standard vancomycin powder should provide the following MIC values noted in Table 2. For the diffusion technique using the 30 mcg vancomycin disk, the criteria in Table 2 should be achieved.

Table 2. In Vitro Susceptibility Test Quality Control Ranges for Vancomycin

Organism ( ATCC#) MIC range (mcg/mL) Disk diffusion range (mm)
Enterococcus faecalis (29212) 1-4 Not applicable
Staphylococcus aureus (29213) 0.5-2 Not applicable
Staphylococcus aureus (25923)a Not applicable 17 - 21
Streptococcus pneumoniae (49619)b,c 0.12-0.5 20 - 27
a Quality control strain and interpretive criteria for testing vancomycin susceptibility of enterococci spp.
b Interpretative criteria applicable only to tests performed using cation-adjusted Mueller-Hinton broth with 2 to 5% lysed horse blood.1 Disk diffusion interpretative criteria applicable only to tests performed using Mueller-Hinton agar with 5% defibrinated sheep blood and incubated in 5% CO2. 2
c Quality control strain and interpretive criteria for testing vancomycin susceptibility of Streptococci spp. other than S. pneumoniae.

Animal Pharmacology

In animal studies, hypotension and bradycardia occurred in dogs receiving an intravenous infusion of vancomycin 25 mg/kg, at a concentration of 25 mg/mL and an infusion rate of 13.3 mL/min.

REFERENCES

1. Clinical and Laboratory Standards Institute (CLSI). Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically; Approved Standard - Tenth Edition. CLSI document M07-A10, Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA, 2015.

2. Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial Susceptibility Testing; Twenty-fifth Informational Supplement, CLSI document M100-S25, Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA, 2015.

3. Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial Disk Diffusion Susceptibility Tests; Approved Standard – Twelfth Edition. CLSI document M02-A12, Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA, 2015.

Last reviewed on RxList: 10/17/2016
This monograph has been modified to include the generic and brand name in many instances.

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