Vancomycin Hydrochloride Capsules - Pharmaceutical Information, Clinical Trials, Detailed Pharmacology, Toxicology
Россия
  • Россия
  • Украина

Vancomycin Hydrochloride Capsules - Scientific Information

Manufacture: Fresenius Kabi USA, LLC
Country: Canada
Condition: Bacteremia, Bacterial Endocarditis Prevention (Bacterial Endocarditis Prophylaxis), Bacterial Infection, Bone infection (Osteomyelitis), Methicillin-Resistant Staphylococcus Aureus Infection, Pneumonia, Sepsis, Skin or Soft Tissue Infection, Surgical Prophylaxis
Class: Glycopeptide antibiotics
Form: Rectal, Capsules
Ingredients: Vancomycin Hydrochloride

Chemistry

Trade Name: Vancomycin Hydrochloride Capsules, USP
Proper Name: Vancomycin hydrochloride
Chemical Name: (Sa)-(3S,6R,7R,22R,23S,26S,36R,38aR)-44-[[2-0-(3-Amino-2,3, 6-trideoxy-3-C-methyl-α-L-lyxo-hexopyranosyl)-β-D-glucopyranosyl] 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: C66H75Cl2N9O24.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

Vancomycin Hydrochloride Capsules, USP contain vancomycin hydrochloride, (expressed in terms of free base) and Polyethylene Glycol 6000. The capsules also contain FD&C Blue No.2, gelatin, iron oxide, polyethylene glycol, and titanium dioxide.

Stability and Storage Recommendations

Store at controlled temperature of 15°C to 25°C. Protect from moisture. Keep out of reach of children.

Availability of Dosage Forms

Vancomycin Hydrochloride Capsules, USP capsules equivalent to 125 mg (0.08 mmol) vancomycin and 250 mg (0.17 mmol) vancomycin are available in (unit-dose) packages of 20 capsules.

Vancomycin Hydrochloride Capsules, USP 125 mg: A size 2, grey/light grey hard gelatin capsule with a white to slightly red or slightly brown solid mass.

Vancomycin Hydrochloride Capsules, USP 250 mg: A size 0, green/turquoise hard gelatin capsule with a white to slightly red or slightly brown solid mass.

Microbiology

Cross-resistance has not 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 invitro 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 μg/mL. Staphylococci are generally susceptible to less than 5 μg/mL of vancomycin hydrochloride, but a small proportion of S.aureus strains requires 10 to 20 μg/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 1: In Vitro Activity of Vancomycin
Organism No. of Strains MIC (µg/mL)
Range Median
Staphylococcus aureus 55 1.0 – 2.0 1.0
  101 0.78 – 12.5 3.1
  35 0.25 – 1.0 1.0
Staphylococcus aureus (methicillin-resistant) 22 0.5 – 4.0 0.5
  38 0.3 – 12.0 1.5
  12 0.2 – 3.12 0.4
Streptococcus epidermidis 177 1.56 – 6.25 3.1
  35 0.4 – 3.1 1.6
  27 0.2 – 6.25 3.12
Streptococcus pneumoniae 70 0.125 – 0.5 0.25
Streptococcus pyogenes 12 0.8 – 3.1 1.6
Streptococcus viridans 82 0.39 – 1.56 0.78
Streptococcus group D Enterococci 382 0.8 → 100.0 3.1
Clostridium perfringens 43 0.4 – 1.6 0.8
Clostridium ramosum 49 3.1 – 12.5 6.2
Clostridium difficile 14 < 1.0 < 1.0
  78 1.0 – 4.0  

Methods of Susceptibility Testing

When the standardized method of disc susceptibility testing is used, a 30 µg disc of vancomycin should produce a zone of more than 11 mm when in 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 μg/mL indicates susceptibility to vancomycin.

Assay Methods

Vancomycin serum and tissue levels may be determined by Bennett's agar-well diffusion method. This test can quantitatively measure vancomycin concentrations from 0.5 to 8 µg/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 μg/mL. The second uses minimal salt agar and is capable of detecting vancomycin concentrations from about 0.8 to 25 μg/mL. A modification of this assay permits reliable bioassay for vancomycin (in concentrations of 0.78 to 50.0 μg/mL) in the presence of rifampin or aminoglycosides. Two commercially prepared assay methods are now available and include a radioimmunoassay and an automated fluorescence polarization immunoassay.

Pharmacology

Human Pharmacology

Adults

Renal Insufficiency

Infusions of 1 g vancomycin in 250 mL D5W 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 μg/mL. The elimination half-life was about 7.5 days.

Oral Administration

Vancomycin is poorly absorbed after oral administration, only trace amounts being found in blood or urine. Following 125 mg orally 4 times daily, the mean concentration of vancomycin in stools was approximately 350 μg/g. Following up to ten daily oral doses of 2 g, a mean level of 3100 μg/g with a range of 905 - 8760 μg/g was detected in feces of patients with pseudomembranous colitis.

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 μg/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 2: LD50 ± SE (mg/kg) following vancomycin administration
Route of Administration Rat Mouse Dog
Intravenous 319 ± 14 489 ± 41 292 ± 29
Intraperitoneal 2218 ± 240 1734 ± 227  
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.