Singapore Drugs Database

Indication

A variety of dosage forms (for example, oral, injections, etc.) exist for the treatment of serious or severe infections caused by susceptible strains of methicillin-resistant (beta-lactam-resistant) staphylococci [FDA Label]. Additionally, a unique FDA approved oral liquid treatment is also available and indicated for the treatment of Clostridium difficile associated diarrhea and enterocolitis caused by _Staphylococcus aureus_, including methicillin-resistant strains [L1196].

Mechanism of Action

The bactericidal action of vancomycin results primarily from inhibition of cell-wall biosynthesis. Specifically, vancomycin prevents incorporation of N-acetylmuramic acid (NAM)- and N-acetylglucosamine (NAG)-peptide subunits from being incorporated into the peptidoglycan matrix; which forms the major structural component of Gram-positive cell walls. The large hydrophilic molecule is able to form hydrogen bond interactions with the terminal D-alanyl-D-alanine moieties of the NAM/NAG-peptides. Normally this is a five-point interaction. This binding of vancomycin to the D-Ala-D-Ala prevents the incorporation of the NAM/NAG-peptide subunits into the peptidoglycan matrix. 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. [L1198, FDA Label]

Pharmacokinetics

Absorption

Poorly absorbed from gastrointestinal tract, however systemic absorption (up to 60%) may occur following intraperitoneal administration [FDA Label].

Distribution

The volume of distribution, as discussed in the literature, varies between 0.4-1 L/kg [A31720].

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 [FDA Label, A31723]. 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 [A31723].

Elimination

Clearance

The mean plasma clearance of vancomycin is about 0.058 L/kg/h [FDA Label].

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. [FDA Label] Conversely, the most common adverse effects associated with vancomycin appear to be nausea, abdominal pain, and hypokalemia [FDA Label]. 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 [FDA Label]. 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 [FDA Label]. Risk of such nephrotoxicity is increased in patients greater than 65 years of age [FDA Label]. 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 [FDA Label]. Potentially related adverse effects like vertigo, dizziness, and tinnitus have also been reported [FDA Label]. 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 [FDA Label]. 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 [FDA Label, A760]. 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 [FDA Label]. 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 [FDA Label]. The safety and effectiveness in pediatric patients have not been formally established [FDA Label]. 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 [FDA Label]. 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 [FDA Label].

Active Ingredient/Synonyms

(1S,2R,18R,22S,25R,28R,40S)-22-(2-amino-2-oxoethyl)-48-[2-O-(3-amino-2,3,6-trideoxy-3-methyl-α-L-lyxo-hexopyranosyl)-β-D-glucopyranosyloxy]-5,15-dichloro-2,18,32,35,37-pentahydroxy-19-[(N-methyl-D-leucyl)amino]-20,23,26,42,44-pentaoxo-7,13-dioxa-21,24,27,41,43-pentaazaoctacyclo[26.14.2.23,6.214,17.18,12.129,33.010,25.034,39]pentaconta-3,5,8(48),9,11,14,16,29(45),30,32,34,36,38,46,49-pentadecaene-40-carboxylic acid | (2.2Sp,3.5Sa,2.6Sp)-O4.2,C3.4:C5.4,O4.6:C3.5,C2.7-tricyclo[N-methyl-D-leucyl-3-chloro-(R)-β-hydroxy-D-tyrosyl-L-asparaginyl-D-2-(4-{[2-O-(3-amino-2,3,6-trideoxy-3-C-methyl-α-L-lyxo-hexopyranosyl)-β-D-glucopyranosyl]oxy}phenyl)glycyl-D-2-(4-hydroxyphenyl)glycyl-3-chloro-(R)-β-hydroxy-L-tyrosyl-L-2-(3,5-dihydroxyphenyl)glycine] | Vancomicina | Vancomycine | Vancomycinum | Vancomycin |