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 two hours after infusion, and mean plasma concentrations of about 10 mcg/mL six 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 microorganism
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 Tests Methods
When available, the clinical microbiology laboratory should provide the results 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 procedure. Standardized procedures are based on a dilution method1,2 (broth, agar or microdilution) or equivalent using standardized inoculum concentrations and concentrations of vancomycin powder. The MIC values should be interpreted according to the criteria 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. One such standardized procedure2,3 requires the use of standardized inoculum concentrations. This procedure uses paper disks impregnated with 30 mcg of vancomycin to test the susceptibility of microorganisms to vancomycin. Interpretation involves correlation of the diameter obtained in the disk test with the MIC for vancomycin. Reports from the laboratory providing results of the standard single-disk susceptibility test with a 30 mcg vancomycin disk should be interpreted according to the following criteria 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 a | ≤4 | 8-16 | ≥32 | ≥17b | 15-16b | ≤14b |
| Staphylococcus aureus | ≤2 | 4-8 | ≥16 | ≥15c | - | - |
| Coagulase- negative staphylococci | ≤4 | 8-16 | ≥32 | ≥15c | - | - |
| Streptococci other than S. pneumoniae | ≤1c,d | - | - | ≥17c,e | - | - |
| a A ß-lactamase test using an inoculum ≥ 107 CFU/mL or direct colony growth and nitrocefin-based substrate should be performed to detect either ampicillin or penicillin resistance due to ß-lactamase production. |
| b Plates should be held for full 24 hours and examined using transmitted light. The presence of haze or any growth within the zone of inhibition indicates resistance. Those enterococci with intermediate zones of inhibition should be tested by standardized procedure based on dilution method1,2 (broth or agar) or equivalent. |
| c The current absence of resistant isolates precludes defining results other than “Susceptible”. Isolates yielding results suggestive of “Nonsusceptible” should be submitted to reference laboratory for further testing. |
| d Interpretative criteria applicable only to tests performed by broth microdilution method using cation-adjusted Mueller-Hinton broth with 2 to 5% lysed horse blood1,2. |
| e Interpretative criteria applicable only to tests performed by disk diffusion method using Mueller-Hinton agar with 5% defibrinated sheep blood and incubated in 5% CO23. |
A report of “Susceptible” indicates that the pathogen is likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable. A report of “Intermediate” 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” indicates that the pathogen is not likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable; other therapy should be selected.
Quality Control
Standardized susceptibility test procedures require the use of laboratory control microorganisms 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. Standard vancomycin powder should provide MIC values provided below. For the diffusion technique, the 30 mcg vancomycin disk should provide the following zone diameters with the quality control strains:
| Table 2. In Vitro Susceptibility Test Quality Control Ranges for Vancomycin |
| Organism (ATTC #) | 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) | Not applicable | 17 - 21 |
| Streptococcus pneumoniae (49619)a | 0.12-0.5 | 20 – 27 |
| a Interpretative criteria applicable only to tests performed using cation-adjusted Mueller-Hinton broth with 2 to 5% lysed horse blood1. Disk diffusion interpretative criteria applicable only to tests performed using Mueller- Hinton agar with 5% defibrinated sheep blood and incubated in 5% CO22. |
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.
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