Vancomycin
- CAS NO.:1404-90-6
- Empirical Formula: C66H75Cl2N9O24
- Molecular Weight: 1449.25
- MDL number: MFCD05664587
- EINECS: 215-772-6
- SAFETY DATA SHEET (SDS)
- Update Date: 2024-11-20 15:18:15
What is Vancomycin?
Absorption
Poorly absorbed from gastrointestinal tract, however systemic absorption (up to 60%) may occur following intraperitoneal administration .
Toxicity
The oral LD50 in mice is 5000 mg/kg. The median lethal intravenous dose is 319 mg/kg in rats and 400 mg/kg in mice.
Conversely, the most common adverse effects associated with vancomycin appear to be nausea, abdominal pain, and hypokalemia . In particular, incidences of hypokalemia, urinary tracy infection, peripheral edema, insomnia, constipation, anemia, depression, vomiting, and hypotension are higher among subjects >65 years of than in those that are 65 years old or younger .
Additionally, nephrotoxicity involving reports of renal failure, renal impairment, elevated blood creatinine, and others has also occurred with vancomycin therapy during studies, and can occur during or after completion of a course of therapy . Risk of such nephrotoxicity is increased in patients greater than 65 years of age .
Ototoxicity has also occurred in patients receiving vancomycin treatment, and it can be transient or permanent. This effect has been reported primarily in patients who have been given excessive intravenous doses, who have kidney dysfunction, who have an underlying hearing loss, or who are receiving concomitant therapy with another ototoxic agent like an aminoglycoside . Potentially related adverse effects like vertigo, dizziness, and tinnitus have also been reported .
Neutropenia, often beginning one week or more after onset of intravenous vancomycin therapy or after a total dose of more than 25 mg has been observed for several dozen patients as well. This neutropenia however, appears to be promptly reversible when the vancomycin treatment is discontinued. Alternatively, thrombocytopenia has also been reported .
Additionally, a condition has been reported that is described as being similar to IV-induced symptoms involving symptoms consistent with anaphylactoid reactions, including hypotension, wheezing, dyspnea, urticaria, pruritus, flushing of the upper body (in what is known as the so-called 'Red Man Syndrome'), pain and muscle spasm of the chest and back. Although on average such reactions usually resolve within 20 minutes, they are just as likely to persist for hours .
In a controlled clinical study, the potential ototoxic and nephrotoxic effects of vancomycin on infants were assessed when the drug was given intravenously to pregnant women for serious staphylococcal infections complicating intravenous drug abuse. The results obtained demonstrated that vancomycin was found in cord blood but that no sensorineural hearing loss or nephrotoxicity attributable to vancomycin was noted. Ultimately however, because the number of subjects treated in this study was limited and vancomycin was administered only in the second and third trimesters, it is not formally known whether vancomycin causes fetal harm. Subsequently, vancomycin should be given to a pregnant woman only if clearly needed .
Although it is known that vancomycin is excreted in human milk based on information obtained from the intravenous administration of the medication, it is not known if vancomycin is excreted into human milk after oral administration. However, because of the overall potential for adverse events, caution must be exercised when vancomycin is given to a nursing woman and a decision must be made whether to discontinue nursing or discontinue the drug, taking into consideration the importance of the drug to the mother .
The safety and effectiveness in pediatric patients have not been formally established .
Patients older than 65 years of age may take longer to respond to therapy compared to patients aged 65 year or younger. Vancomycin treatment in patients aged older than 65 years subsequently should not be discontinued or switched to an alternative treatment prematurely .
Furthermore, clinical studies have demonstrated that geriatric patients are at increased risk of developing nephrotoxicity following treatment with oral vancomycin, which can occur during or after completion of therapy. In patients aged older than 65 years, including those with normal renal function prior to treatment, renal function should be monitored during and following treatment with vancomycin to detect any potential vancomycin induced nephrotoxicity .
Description
Vancomycin is produced by fermentation of Amycol atopsis orientalis (formerly Nocardi a orientalis). It has been available for approximately 40 years, but its popularity has increased significantly with the emergence of MRSA in the early 1980s. Chemically, vancomycin has a glycosy lated hexapeptide chain that is rich in unusual amino acids, many of which contain aromatic rings cross-linked by aryl ether bonds into a rigid molecular framework.
Description
Vancomycin is an amphoteric glycopeptide antibiotic produced by the soil bacterium?Amycolatopsis orientalis. It is mainly used to treat serious Gram-positive bacterial infections that do not respond to other antibiotics. For most infections, it is administered intravenously because it is poorly absorbed from the gut. But it is given orally to treat some types of colitis.
In 1955, Mack H. McCormick and colleagues at Eli Lilly isolated vancomycin from?A. orientalis?(then called?Streptomyces orientalis). Its highly complex structure was not finally determined until 1981. David A. Evans and co-workers at Harvard and K. C. Nicolaou and colleagues at the Scripps Research Institute reported the total synthesis of vancomycin in 1998 and 1999, respectively.
Vancomycin is not the answer to all antibiotic resistance problems. Some Gram-positive bacteria are intrinsically resistant to it; but more significantly, bacteria once susceptible to vancomycin are gradually becoming resistant to it, especially in hospitals and other health care institutions. Research to develop alternatives to vancomycin has been in progress for more than 20 years.
Nonetheless, vancomycin is as important as ever because it is used to treat the urgent threat of?Clostridium difficile?colitis and the serious threat of?Staphylococcus aureus?infections. For more on bacterial resistance to antibiotics, see the update on tetracycline.
Originator
Vancocin,Lilly,US,1958
The Uses of Vancomycin
Vancomycin is used for serious bacterial infections caused by microorganisms sensitive to this drug when penicillins and cephalosporins are ineffective for diseases such as sepsis, endocarditis, pneumonia, pulmonary abscess, osteomyelitis, meningitis, and enterocolitis, or when penicillins and cephalosporins cannot be tolerated by patients. Vancomycin is the drug of choice for infections caused by methicillin-resistant forms of S. aureus, S. epidermidus, and other coagulase-negative staphylococci, as well as for endocarditis, diphtherioid infections, and for patients very sick with colitis caused by C. difficile. A synonym of this drug is vancocin.
The Uses of Vancomycin
Antibacterial.
Background
Antibacterial obtained from Streptomyces orientalis. It is a glycopeptide related to ristocetin that inhibits bacterial cell wall assembly and is toxic to kidneys and the inner ear.
As of January 29 2018, CutisPharma's Firvanq is the only FDA approved vancomycin oral liquid treatment option available for the the treatment of Clostridium difficile associated diarrhea and enterocolitis caused by Staphylococcus aureus, including methicillin-resistant strains [LP1196]. Such an oral liquid formulation is expected to make Clostridium difficile associated diarrhea therapy more accessible in comparison to previously available specialty compounding products [LP1196].
Indications
Administered intravenously, vancomycin is indicated in adult and pediatric patients for the treatment of septicemia, infective endocarditis, skin and skin structure infections, bone infections, and lower respiratory tract infections. Administered orally, vancomycin is indicated in adult and pediatric patients for the treatment of Clostridium difficile-associated diarrhea and for enterocolitis caused by Staphylococcus aureus (including methicillin-resistant strains).
Definition
ChEBI: A complex glycopeptide from Streptomyces orientalis. It inhibits a specific step in the synthesis of the peptidoglycan layer in the Gram-positive bacteria Staphylococcus aureus and Clostridium difficile.
Manufacturing Process
An agar slant is prepared containing the following ingredients: 20 grams
starch, 1 gram asparagine, 3 grams beef extract, 20 grams agar, and 1 liter
water. The slant is inoculated with spores of S. orientalis, Strain M43-05865,
and is incubated for about 10 days at 30°C. The medium is then covered with
sterile distilled water and scraped to loosen the spores. The resulting
suspension of spores is preserved for further use in the process.
A liquid nutrient culture medium is prepared containing the following
ingredients: 15 grams glucose, 15 grams soybean meal, 5 grams corn steep
solids, 2 grams sodium chloride, 2 grams calcium carbonate, and 1 liter water.
The medium is sterilized at 120°C for about 30 minutes in a suitable flask and
cooled. 10 ml of a spore suspension prepared as set forth above are used to
inoculate the medium. The inoculated medium is shaken for 48 hours at 26°C on a reciprocating shaker having a 2-inch stroke, at 110 rpm.
The fermented culture medium which comprises a vegetative inoculum is used
to inoculate a nutrient culture medium containing the following ingredients: 20
grams blackstrap molasses, 5 grams soybean peptone, 10 grams glucose, 20
grams sucrose, 2.5 grams calcium carbonate, and 1 liter water.
The medium is placed in a container having a suitable excess capacity in order
to insure the presence of sufficient oxygen and is sterilized by heating at
120°C for about 30 minutes. When cool, the medium is inoculated with about
25 ml of a vegetative inoculum as described above, and the culture is then
shaken for about 80 hours at 26°C. The pH of the medium at the beginning of
fermentation ranges from about 6.5 to about 7.0 and the final pH is about 7.0
to about 8.0. A fermentation broth thus obtained contained about 180 μg of
vancomycin per ml.
brand name
Vancocin Hydrochloride (ViroPharma); Vancoled (Baxter Healthcare); Vancor (Pharmacia & Upjohn).
Therapeutic Function
Antibacterial
Acquired resistance
Only very recently, despite decades of intensive use, have some vancomycin-resistant bacteria emerged (vancomycin-resistant enterococcus [VRE] and vancomycin-resistant Staphylococcus aureus) [VRSA]. It is alleged that these resistant strains emerged as a consequence of the agricultural use of avoparcin, a structurally related antibiotic that has not found use for human infections in the United States but was used in Europe before its recent ban. The mechanism of resistance appears to be alteration of the target D-alanyl-D-alanine units on the peptidoglycan cell wall precursors to D-alanyl-D-lactate. This results in lowered affinity for vancomycin due to lack of a key hydrogen bonding interaction. It is greatly feared that this form of resistance will become common in the bacteria for which vancomycin is presently the last sure hope for successful chemotherapy. If so, such infection would become untreatable. These resistant strains are not yet common in clinically relevant strains, but most authorities believe that this is only a question of time. Vancomycin-intermediate S.aureus, also called glycoprotein-intermediate S.aureus (VISA), also has been reported. It appears to be resistant because of a thickened peptidoglycan layer.
Mechanism of action
Vancomycin is a bacterial cell wall biosynthesis inhibitor. Evidence suggests that the active species is a homodimer of two vancomycin units. The binding site for its target is a peptide-lined cleft having high affinity for acetyl-D-alanyl-D-alanine and related peptides through five hydrogen bonds. It inhibits both transglycosylases (inhibiting the linking between muramic acid and acetyl glucosamine units) and transpeptidase (inhibiting peptide cross-linking) activities in cell wall biosynthesis. Thus, vancomycin functions like a peptide receptor and interrupts bacterial cell wall biosynthesis at the same step as the β-lactams do, but by a different mechanism. By covering the substrate for cell wall transamidase, it prevents cross-linking resulting in osmotically defective cell walls.
Pharmacokinetics
Vancomycin is a branched tricyclic glycosylated nonribosomal peptide often reserved as the "drug of last resort", used only after treatment with other antibiotics has failed. Vancomycin has been shown to be active against most strains of the following microorganisms, both in vitro and in clinical infections: Listeria monocytogenes, Streptococcus pyogenes, Streptococcus pneumoniae (including penicillin-resistant strains), Streptococcus agalactiae, Actinomyces species, and Lactobacillus species. 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 .
Clinical Use
Although a number of adverse effects can result from IV infusion, vancomycin has negligible oral activity. It can be used orally for action in the GI tract, especially in cases of Cl ostri di um difficile overgrowth. The useful spectrum is restricted to Gram-positive pathogens, with particular utility against multiply-resistant, coagulase-negative staphylococci and MRSA, which causes septicemias, endocarditis, skin and soft-tissue infections, and infections associated with venous catheters.
Clinical Use
Vancomycin was discovered, developed, and approved by the US Food and Drug Administration in the 1950s. In 1956, it was introduced in the USA as a possible treatment for infections due to penicillinresistant S. aureus, but it was not used widely because of toxicity and the nearly simultaneous development of semisynthetic antibiotics and cephalosporins. Thus, its main indication was the treatment of serious Gram-positive infections in penicillin-allergic patients. In clinical practice, however, nafcillin remained the treatment of choice for staphylococcal bacteremia, largely because it had failure rates of only 4%. With the appearance of methicillin-resistant S. aureus and coagulase-negative staphylococci, vancomycin became the drug of choice for these infections. With the recognition and/or emergence of S. aureus strains (generally MRSA isolates) with reduced susceptibility to vancomycin 586 Glycopeptides and Lipopeptides, vancomycin efficacy may be less in some clinical situations than previously reported – especially in serious deep-seated infections, such as endocarditis and prosthetic device infections. This is demonstrated by increased mortality seen in patients with MRSA infection and markedly attenuated vancomycin efficacy caused by vancomycin heteroresistance in S. aureus. Resistance of S. aureus to vancomycin can be a continuous phenomenon, rather than a categorical one. Thus, this has resulted in some clinical microbiology laboratories having difficulty identifying S. aureus strains that have reduced vancomycin susceptibility based on standard laboratory susceptibility testing methodology. A better understanding is still needed of the pharmacodynamic relationship between vancomycin and MRSA as relates to optimal dosing strategies, including consideration of loading doses.
Side Effects
Vancomycin is highly associated with adverse infusion-related events. These are especially prevalent with higher doses and a rapid infusion rate. A rapid infusion rate has been shown to cause anaphylactoid reactions, including hypotension, wheezing, dyspnea, urticaria, and pruritus. A significant drug rash (the so-called red man syndrome) also can occur. These events are much less frequent with a slower infusion rate. In addition to the danger of infusion-related events, higher doses of vancomycin can cause nephrotoxicity and auditory nerve damage. The risk of these effects is increased with elevated, prolonged concentrations, so vancomycin use should be monitored, especially in patients with decreased renal function. The ototoxicity may be transient or permanent and more commonly occurs in patients receiving high doses, patients with underlying hearing loss, and patients being treated concomitantly with other ototoxic agents (i.e., aminoglycosides).
Drug interactions
Potentially hazardous interactions with other drugs
Antibacterials: increased risk of nephrotoxicity and
ototoxicity with aminoglycosides, capreomycin or
colismethate sodium; increased risk of nephrotoxicity
with polymyxins.
Ciclosporin: variable response; increased risk of
nephrotoxicity.
Diuretics: increased risk of ototoxicity with loop
diuretics.
Muscle relaxants: enhanced effects of
suxamethonium.
Tacrolimus: possible increased risk of nephrotoxicity
Metabolism
Since almost 75-80% of the drug is excreted unchanged in the urine after the first 24 hours following administration, there is seemingly no apparent metabolism of the drug . The concentration of vancomycin in the liver tissue and bile 24 hours after administration has also been reported at or below detection limits as well .
Metabolism
Little or no metabolism of vancomycin is thought to take place. It is excreted unchanged by the kidneys, mostly by glomerular filtration. There is a small amount of nonrenal clearance, although the mechanism for this has not been determined.
Properties of Vancomycin
Melting point: | >274°C (dec.) |
Density | 1.2882 (rough estimate) |
refractive index | 1.7350 (estimate) |
storage temp. | 2-8°C |
solubility | DMSO (Slightly) |
pka | pKa 2.18±0.08(H2O
t = 25.0±0.1
I = 0.2 (NaCl)
N2 atmosphere) (Uncertain);7.75±0.02(H2O
t = 25.0±0.1
I = 0.2 (NaCl)
N2 atmosphere) (Uncertain);8.89±0.01(H2O
t = 25.0±0.1
I = 0.2 (NaCl)
N2 atmosphere) (Uncertain) |
form | Solid |
color | Off-White |
Stability: | Hygroscopic |
CAS DataBase Reference | 1404-90-6(CAS DataBase Reference) |
Safety information for Vancomycin
Computed Descriptors for Vancomycin
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