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Vancomycin Hydrochloride

Vancomycin is a tricyclic glycopeptide antibiotic that is unrelated to other commercially available antibiotics.

Drug Interactions

Ototoxic and Nephrotoxic Drugs

Because of the possibility of additive toxicities, the concurrent or sequential systemic or topical use of other ototoxic and/or nephrotoxic drugs (e.g., aminoglycosides, amphotericin B, bacitracin, cisplatin, colistin, polymyxin B) and vancomycin requires careful monitoring of renal and auditory functions; these drugs should be used with caution in patients receiving vancomycin therapy.

Acute Toxcicity

Limited information is available on the acute toxicity of vancomycin. The IV LD50 of the drug in rats or mice is 319 or 400 mg/kg, respectively. Treatment of vancomycin overdosage is mainly supportive with maintenance of glomerular filtration. The drug is not appreciably removed by dialysis; however, hemofiltration and hemoperfusion using polysulfone resin reportedly has increased vancomycin clearance.

Mechanism of Action

Vancomycin is bactericidal and appears to bind to the bacterial cell wall causing blockage of glycopeptide polymerization. This effect, which occurs at a site different from that affected by the penicillins, produces immediate inhibition of cell wall synthesis and secondary damage to the cytoplasmic membrane. Magnesium, manganese, calcium, and ferrous ions reduce the degree of adsorption of vancomycin to the cell wall, but the in vivo importance of this interaction is unknown.

Vancomycin Hydrochloride

Spectrum Vancomycin is active against many gram-positive organisms, including staphylococci, Streptococcus pyogenes (group A b-hemolytic streptococci), Streptococcus pneumoniae, enterococci, Corynebacterium, and Clostridium, including C. difficile. The drug is not active against gram-negative organisms, fungi, or yeast. In vitro, vancomycin is bactericidal for most gram-positive organisms at a concentration of less than 5 mcg/mL. Most strains of S. aureus are susceptible to 1.6 mcg of vancomycin per mL or less, although a few strains have been found to be naturally resistant to clinically achievable concentrations of the drug. In vitro studies indicate that the antibacterial activities of vancomycin and streptomycin or gentamicin may be synergistic against enterococci, but the clinical value of this interaction is questionable because of the additive toxicities of these agents.

In Vitro Susceptibility Testing

The National Committee for Clinical Laboratory Standards (NCCLS) states that, if results of in vitro susceptibility testing indicate that a clinical isolate is susceptible to vancomycin, then an infection caused by this strain may be appropriately treated with the dosage of the drug recommended for that type of infection and infecting species, unless otherwise contraindicated. If results indicate that a clinical isolate has intermediate susceptibility to vancomycin, then the strain has a minimum inhibitory concentration (MIC) that approaches usually attainable blood and tissue drug concentrations and response rates may be lower than for strains identified as susceptible.

Therefore, the intermediate category implies clinical applicability in body sites where the drug is physiologically concentrated (e.g., urine) or when a high dosage of the drug can be used. This intermediate category also includes a buffer zone which should prevent small, uncontrolled technical factors from causing major discrepancies in interpretation, especially for drugs with narrow pharmacotoxicity margins.

If results of in vitro susceptibility testing indicate that a clinical isolate is resistant to vancomycin, the strain is not inhibited by systemic concentrations of the drug achievable with usual dosage schedules and/or MICs fall in the range where specific microbial resistance mechanisms are likely and efficacy has not been reliably demonstrated in clinical trials. Strains of staphylococci with reduced susceptibility to vancomycin may not be reliably detected with current disk-diffusion procedures, and it has been recommended that a quantitative method (broth or agar dilution, agar gradient diffusion) be used to evaluate susceptibility of staphylococci to vancomycin.

Disk Susceptibility Tests

When the disk-diffusion procedure is used to test susceptibility to vancomycin, a disk containing 30 mcg/ of vancomycin should be used. When disk-diffusion susceptibility testing is performed according to NCCLS standardized procedures and NCCLS interpretive criteria, Staphylococcus with growth inhibition zones of 15 mm or greater are considered susceptible to vancomycin. All Staphylococcus with growth inhibition zones of 14 mm or less should be tested using a dilution susceptibility test. When the disk-diffusion test is performed according to NCCLS standardized procedures, Enterococcus with growth inhibition zones of 17 mm or greater are susceptible to vancomycin, those with zones of 15-16 mm have intermediate susceptibility, and those with zones of 14 mm or less are resistant to the drug. Accurate detection of vancomycin-resistant enterococci requires that plates be incubated for a full 24 hours and that growth inhibition zones be examined carefully with transmitted light for evidence of small colonies or a light film growing within the zone.

Enterococci isolated from patients with serious infections that are identified as having intermediate susceptibility in the disk-diffusion procedure should then be tested using a dilution susceptibility method.

When testing susceptibility of Streptococcus (including S. pneumoniae) according to NCCLS standardized procedures using Mueller-Hinton agar (supplemented with 5% sheep blood) incubated in 5% CO2, Streptococcus with growth inhibition zones of 17 mm or greater are susceptible to vancomycin. Because of limited data on resistant strains of these organisms, NCCLS recommends that streptococcal isolates that appear to be nonsusceptible to vancomycin should be submitted to a reference laboratory for further testing.

Dilution Susceptibility Tests

When dilution susceptibility testing (agar or broth dilution) is performed according to NCCLS standardized procedures using NCCLS interpretive criteria, Staphylococcus with MICs of 4 mcg/mL or less are susceptible to vancomycin, those with MICs of 8-16 mcg/mL have intermediate susceptibility, and those with MICs of 32 mcg/mL or greater are resistant to the drug.

Because of limited data on resistant strains, NCCLS recommends that any Staphylococcus isolate that has an MIC of 4 mcg/mL or greater should be send to a reference laboratory.

The US Centers for Disease Control and Prevention (CDC) has recommended that, after retesting to confirm species identification and susceptibility results, Staphylococcus with vancomycin MICs of 4 mcg/mL or greater should be reported to the state health department and the CDC Hospital Infections Program, National Center for Infectious Disease ( 404-639-6413) and sent to the CDC for microbiologic and epidemiologic evaluation.

When broth dilution is performed according to NCCLS standardized procedures using NCCLS interpretive criteria, Enterococcus with MICs of 4 mcg/mL or less are susceptible to vancomycin, those with MICs of 8-16 mcg/mL have intermediate susceptibility, and those with MICs of 32 mcg/mL or greater are resistant to the drug. Accurate identification of resistant strains of Enterococcus requires that vancomycin plates be held for a full 24-hour incubation period and that isolates with MICs of 8-16 mcg/mL be tested further using specific biochemical tests.

When broth dilution susceptibility testing of Streptococcus, including S. pneumoniae is performed according to NCCLS standardized procedures using cation-adjusted Mueller-Hinton broth (supplemented with 2-5% lysed horse blood), streptococci with MICs of 1 mcg/mL or less are considered susceptible to vancomycin. Any streptococcal isolate that appears to be nonsusceptible to vancomycin should be submitted to a reference laboratory for further testing.

Resistance

Resistance in Enterococci

Resistance to vancomycin has been reported in Enterococcus faecalis (formerly Streptococcus faecalis), E. faecium (VREF; formerly S. faecium), and E. gallinarum, and strains of enterococci resistant to vancomycin have been reported with increasing frequency.

According to US Centers for Disease Control and Prevention (CDC) surveillance data, since 1989 there has been a 20-fold increase in the percentage of vancomycin-resistant enterococci associated with nosocomial infections in the US176, 200 and a 34-fold increase in the percentage of resistant strains associated with infections in hospital intensive-care units.

Approximately 0.3% of enterococci isolated from nosocomial infections in the US in 1989 were resistant to vancomycin; in 1993, this percentage was 7.9%. Vancomycin-resistant strains of enterococci have been isolated most frequently from GI/intra-abdominal and urinary tract infections, but also have been isolated from skin and soft tissue, bloodstream, and other infections. Several different forms of vancomycin resistance have been identified in enterococci, including high-level resistance and low-level resistance. Strains of enterococci with high-level resistance generally require vancomycin concentrations of 128 mcg/mL or more and strains with low-level resistance generally require concentrations of 16-64 mcg/mL for in vitro inhibition.

High-level vancomycin resistance has been reported in E. faecium and E. faecalis, appears to be plasmid mediated, and can be induced by exposure to vancomycin and, to a lesser extent, exposure to teicoplanin. Low-level vancomycin resistance has been reported in E. faecium, E. faecalis, and E. gallinarum and may also be induced by exposure to vancomycin, but may or may not be induced by exposure to teicoplanin.

The mechanisms of vancomycin resistance in enterococci have not been fully elucidated. High-level vancomycin resistance most frequently has been associated with the presence of a certain protein and a phenotype termed VanA; low-level resistance usually has been associated with the presence of a different phenotype, termed VanB. Two other phenotypes, VanC and VanD, also have been identified. In general, VanA resistance is high level, transferable, and accompanied by high-level teicoplanin resistance. VanB resistance is widely variable in level, transferable, and not accompanied by teicoplanin resistance; VanC resistance is low level, not transferable, and not associated with teicoplanin resistance; and VanD resistance is intermediate level and associated with low-level teicoplanin resistance.

Presence of vancomycin resistance in enterococci, especially low-level resistance, may be difficult to detect with standard in vitro susceptibility tests. Some strains of E. faecium resistant to vancomycin may be susceptible in vitro to linezolid or the fixed combination of quinupristin and dalfopristin; some strains of E. faecalis resistant to vancomycin may be susceptible to linezolid in vitro but these strains are resistant to quinupristin and dalfopristin.

Although strains of enterococci with high-level, plasmid-mediated vancomycin resistance generally are cross-resistant to other glycopeptides, including teicoplanin, ristocetin, and actaplanin, some strains of E. faecalis, E. faecium, E. casseliflavus, E. flavascens, and E. gallinarum with low-level vancomycin resistance may be susceptible to teicoplanin in vitro. Strains of vancomycin-resistant enterococci may also be resistant to other drugs (e.g., aminoglycosides, ampicillin, penicillin G, imipenem, tetracyclines, synergistic combinations of b-lactam anti-infectives). These multidrug-resistant strains of enterococci have been reported with increasing frequency.

Resistance in Staphylococci

Until recently, clinical isolates of Staphylococcus, including methicillin-resistant S. aureus (MRSA), have consistently been susceptible to vancomycin in vitro. However, in vitro exposure of staphylococci to increasing concentrations of glycopeptide anti-infectives can produce strains with decreased susceptibility and emergence of vancomycin-resistant strains of S. haemolyticus and S. epidermidis have been reported rarely in patients receiving the drug.

A strain of MRSA with reduced susceptibility to vancomycin (MIC of 8 mcg/mL) was first identified in 1996 in a Japanese child receiving the drug for a nosocomial surgical site infection. In 1997, the first MRSA isolate with reduced (intermediate) susceptibility to vancomycin was identified in the US in a patient who had received multiple courses of intraperitoneal and IV vancomycin therapy for repeated episodes of MRSA-associated peritonitis.

A second isolate with reduced (intermediate) susceptibility to vancomycin was identified in the US in a patient with diabetes mellitus after 18 weeks of IV vancomycin therapy for MRSA bacteremia. In vitro testing indicated that these isolates had a vancomycin MIC of 8 mcg/mL but were susceptible to rifampin, chloramphenicol, co-trimoxazole, and tetracycline.

Epidemiologic and laboratory investigations are under way to assess the risk for person-to-person transmission of staphylococci with reduced susceptibility to vancomycin and to determine the mechanism of resistance in these strains. In vitro studies indicate that the VanA gene associated with vancomycin resistance in enterococci may be transferable to other gram-positive bacteria, including S. aureus, and can result in vancomycin-resistant strains of this organism. However, polymerase chain reaction testing of at least one isolate of MRSA with reduced susceptibility to vancomycin did not detect the VanA or VanB gene.

Pharmacokinetics

Absorption

Vancomycin hydrochloride is usually not appreciably absorbed from the GI tract; however, limited data suggest that clinically important serum concentrations of the drug may result following enteral or oral administration of vancomycin in some patients with colitis, particularly those who also have renal impairment. Following IV administration of 1 g of the drug to adults, plasma concentrations have been reported to average 25 mcg/mL at 2 hours. Serum vancomycin concentrations are higher in patients with renal dysfunction than in those with normal renal function, and toxic serum concentrations may result.

Distribution

Following IV administration, vancomycin is widely distributed in body tissues and diffuses readily into pericardial, pleural, ascitic, and synovial fluids. Small amounts of the drug are distributed into bile. Vancomycin does not readily distribute into CSF in the absence of inflammation unless serum concentrations are exceedingly high. In most studies in patients with uninflamed meninges, no or only negligible amounts of the drug were detected in CSF.

Low concentrations of the drug may be present in CSF if meninges are inflamed. In a limited number of adults and children with meningitis who received IV vancomycin in a dosage of 10-15 mg/kg daily, average CSF concentrations 1-3 hours after a dose were 3.3-3.8 mcg/mL and were 21-22% of concurrent serum concentrations. However, the relationship between CSF concentrations and clinical efficacy of vancomycin in the treatment of meningitis is unclear. Vancomycin diffuses readily across the placenta and is distributed into cord blood. It is not known whether vancomycin is distributed into milk. At a concentration of 10-100 mcg/mL in vitro, vancomycin is reportedly 52-60% bound to serum proteins.

Elimination

The serum elimination half-life of vancomycin in adults with normal renal function has been reported to average 4-6 hours; accumulation tends to occur after 2-3 days of IV administration at 6- or 12-hour intervals. Serum elimination half-life is increased in patients with renal dysfunction. In one study, the elimination half-life averaged 32.3 hours (range: 10.1-75.1 hours) in patients with a creatinine clearance of 10-60 mL/minute and 146.7 hours (range: 44.1-406.4 hours) in patients with a creatinine clearance of less than 10 mL/minute. Parenterally administered vancomycin is excreted primarily by glomerular filtration.

More than 80% of a single IV dose is excreted within 24 hours. Specific urinary concentrations of the drug have not been determined. Only small amounts of vancomycin are excreted in the bile following IV administration.

Oral doses are excreted primarily in the feces. Vancomycin is only minimally removed by hemodialysis or peritoneal dialysis, including continuous ambulatory peritoneal dialysis. The drug is substantially removed by hemofiltration.

Chemistry and Stability

Chemistry

Vancomycin is a tricyclic glycopeptide antibiotic obtained from cultures of Nocardia orientalis (formerly Streptomyces orientalis). Vancomycin is structurally unrelated to other commercially available antibiotics. Vancomycin is commercially available as the hydrochloride salt; however, potency of commercially available vancomycin hydrochloride is expressed in terms of vancomycin. Vancomycin hydrochloride occurs as an amphoteric, tan to brown, free-flowing powder with a bitter taste.

The drug is freely soluble in water and insoluble in alcohol. A 5% aqueous solution of vancomycin hydrochloride has a pH of 2.5-4.5. The commercially available frozen vancomycin hydrochloride injections containing 500 mg of vancomycin in approximately 5% dextrose injection are frozen, nonpyrogenic, sterile, iso-osmotic solutions of the drug; hydrochloric acid and, possibly, sodium hydroxide have been added to adjust pH to 3-5.

Stability

Commercially available vancomycin hydrochloride capsules, powder for oral solution, and powder for IV administration should be stored at 15-30°C. The manufacturer states that the stability of the commercially available frozen vancomycin hydrochloride injection in dextrose may vary; these injections are stable for at least 90 days from the date of shipment when stored at a temperature not greater than -20°C.

When reconstituted with sterile water for injection, vancomycin hydrochloride injection is reportedly stable for 2 weeks at room temperature; the manufacturers state that reconstituted injections may be stored for 96 hours at 2-8°C without substantial loss of potency. When reconstituted as directed in 0.9% sodium chloride injection or 5% dextrose injection, solutions prepared from ADD-Vantage® vials of the drug are stable for 24 hours at room temperature. Vancomycin solutions containing 5 mg/mL in 0.9% sodium chloride injection or 5% dextrose injection are reportedly stable for at least 17 days when stored at 24°C in glass or PVC containers and for at least 63 days when stored at 5°C or -10°C in glass containers.

Following reconstitution with sterile water for injection as directed, vancomycin solutions that have been further diluted to a concentration of 5 mg/mL in 5-30% dextrose injection are stable when stored in plastic syringes for 24 hours at 4°C and then subsequently for 2 hours at room temperature. The commercially available frozen injection of vancomycin should be thawed at room temperature (25°C) or under refrigeration (5°C) and, once thawed, should not be refrozen.

Thawed solutions of the commercially available frozen injection are stable for 72 hours at room temperature (25°C) or 30 days when refrigerated at 5°C. The commercially available frozen injection of the drug in dextrose is provided in a plastic container fabricated from specially formulated multilayered plastic PL 2040 (Galaxy®). Solutions in contact with the plastic can leach out some of its chemical components in very small amounts within the expiration period of the injection; however, safety of the plastic has been confirmed in tests in animals according to USP biological tests for plastic containers as well as by tissue culture toxicity studies.

Lilly states that reconstituted vancomycin hydrochloride oral solutions may be stored at 2-8°C for 2 weeks without substantial loss of potency; other data indicate that reconstituted oral solutions are stable for at least 90 days when stored at 0° or 4°C. Vancomycin hydrochloride injection has been reported to be physically incompatible with many drugs (especially alkaline injections), but the compatibility depends on several factors (e.g., concentrations of the drugs, specific diluents used, resulting pH, temperature).

Specialized references should be consulted for specific compatibility information. Ophthalmic solutions that have been prepared extemporaneously by diluting vancomycin hydrochloride sterile powder with artificial tears (i.e., Liquifilm® Tears, Tears Naturale®) to a final vancomycin concentration of 31-50 mg/mL have been reported to have variable pH and stability.

In one study in which the drug was diluted with 10 mL of artificial tears to provide a resultant concentration of 50 mg/mL, recommendations concerning stability and storage were not possible since pH of the resultant ophthalmic solution decreased rapidly to less than 3.5 by the seventh day, a pH that would not be tolerated by the eye. In another study in which the sterile powder initially was diluted with 5 mL of sterile water for injection to a concentration of 100 mg/mL and then further diluted to a concentration of 31 mg/mL by withdrawing 4.6 mL of this solution and diluting it in approximately 10.4 mL of artificial tears, no substantial change in pH occurred (3.7-5) over time, but the final solution had a pH of 5 and would likely be irritating to the eye. In this study, vancomycin was stable for 45 days at -10°C, 10 days at 4°C, and 7 days at 25°C.

Preparations

Vancomycin Hydrochloride Oral Capsules 125 mg (of vancomycin) Vancocin® HCl Pulvules®, Lilly 50 mg (of vancomycin) Vancocin® HCl Pulvules®, Lilly For solution 1 g (of vancomycin) Vancocin® HCl, Lilly 10 g (of vancomycin) Vancocin® HCl, (with alcohol 40 mg/g) Lilly Parenteral For injection 5 g (of vancomycin) pharmacy Vancomycin Hydrochloride for bulk package Injection, Abbott American Pharmaceutical Partners Lederle 10 g (of vancomycin) Vancocin® HCl for Injection, pharmacy bulk package (with alcohol and edetate calcium disodium) Lilly Vancomycin Hydrochloride for Injection, American Pharmaceutical Partners For injection, for 500 mg (of vancomycin) Vancocin® HCl IntraVenous, IV infusion Lilly Vancocin® HCl IntraVenous ADD-Vantage®, Lilly Vancomycin Hydrochloride for Injection, American Pharmaceutical Partners Elkins-Sinn Hospira Lederle Vancomycin Hydrochloride Sterile ADD-Vantage®, Hospira 1 g (of vancomycin)  Vancocin® HCl IntraVenous, Lilly Vancocin® HCl IntraVenous ADD-Vantage®, Lilly Vancomycin Hydrochloride for Injection, American Pharmaceutical Partners Elkins-Sinn Hospira Lederle Vancomycin Hydrochloride for Injection ADD-Vantage®, Hospira Vancomycin Hydrochloride in Dextrose Parenteral Injection (frozen) 5 mg (of vancomycin) per ml Vancocin® HCl in Iso-osmotic , for IV infusion (500 mg) in 5% Dextrose Dextrose Injection, (Galaxy®[Baxter]) Lilly

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