Vancomycin Totally Explained

Everything about Vancomycin totally explained

| PubChem=14969 | DrugBank=APRD01287 | C=66 | H=75 | Cl=2 | N=9 | O=24 | molecular_weight = 1449.3 g.mol^-1 | bioavailability= Negligible (oral) | metabolism = Excreted unchanged | elimination_half-life=4–11 hours (adults)
6-10 days (adults, impaired renal function) | excretion = Renal | pregnancy_category = B2 (Au), B (U.S.) | legal_status = S4 (Au), POM (UK), ℞-only (U.S.) | routes_of_administration= IV, oral }} Vancomycin (INN) is a glycopeptide antibiotic used in the prophylaxis and treatment of infections caused by Gram-positive bacteria. It has traditionally been reserved as a drug of "last resort", used only after treatment with other antibiotics had failed, although the emergence of vancomycin-resistant organisms means that it's increasingly being displaced from this role by linezolid and the carbapenems.

History

Vancomycin was first isolated by EC Kornfeld (working at Eli Lilly) from a soil sample collected from the interior jungles of Borneo by a missionary. The organism that produced it was eventually named Amycolatopsis orientalis. The original indication for vancomycin was for the treatment of penicillin-resistant Staphylococcus aureus.
The compound was initially labelled compound 05865, but was eventually given the generic name, vancomycin (derived from the word "vanquished"). One advantage that was quickly apparent was that staphylococci didn't develop significant resistance despite serial passage in culture media containing vancomycin. The rapid development of penicillin-resistance by staphylococci led to the compound being fast-tracked for approval by the FDA in 1958. Eli Lilly first marketed vancomycin hydrochloride under the trade name Vancocin. these findings led to vancomycin being relegated to the position of a drug of last resort. In 2004, Eli Lilly licensed Vancocin to ViroPharma in the U.S., Flynn Pharma in the UK and Aspen Pharmacare in Australia. The patent expired in the early 1980s and generic versions of the drug are also available under various trade names.

Pharmacology and chemistry

It is a branched glycosylated nonribosomal peptide produced by the fermentation of the Actinobacteria species Amycolatopsis orientalis (formerly designated Nocardia orientalis).
   Vancomycin acts by inhibiting proper cell wall synthesis in Gram-positive bacteria. The mechanism inhibited, and various factors related to entering the outer membrane of Gram-negative organisms mean that vancomycin isn't active against Gram-negative bacteria (except some non-gonococcal species of Neisseria).
   Specifically, vancomycin prevents incorporation of N-acetylmuramic acid (NAM)- and N-acetylglucosamine (NAG)-peptide subunits 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.
   Vancomycin exhibits atropisomerism — it has two chemically distinct rotamers owing to the rotational restriction of the chlorotyrosine residue (on the right hand side of the figure). The form present in the drug is the thermodynamically more stable conformer, and, importantly, has more potent activity.
   Vancomycin can be given orally, but this method is very expensive. It may also be used in treatment for clostridium difficile.

Clinical use

Indications

Vancomycin is indicated for the treatment of serious, life-threatening infections by Gram-positive bacteria which are unresponsive to other less toxic antibiotics. In particular, vancomycin shouldn't be used to treat methicillin-sensitive Staphylococcus aureus because it's inferior to penicillins such as nafcillin.
The increasing emergence of vancomycin-resistant enterococci has resulted in the development of guidelines for use by the Centers for Disease Control (CDC) Hospital Infection Control Practices Advisory Committee. These guidelines restrict use of vancomycin to the following indications:

treatment of serious infections caused by susceptible organisms resistant to penicillins (methicillin-resistant Staphylococcus aureus and multi-resistant Staphylococcus epidermidis (MRSE)) or in individuals with serious allergy to penicillins

pseudomembranous colitis (relapse or unresponsive to metronidazole treatment)

For treatment of infections caused by gram-positive microorganisms in patients who have serious allergies to beta-lactam antimicrobials. (http://wonder.cdc.gov/wonder/prevguid/m0039349/m0039349.asp)

antibacterial prophylaxis for endocarditis following certain procedures in penicillin-hypersensitive individuals at high risk

surgical prophylaxis for major procedures involving implantation of prostheses in institutions with a high rate of MRSA or MRSE

Adverse effects

Common adverse drug reactions (≥1% of patients) associated with IV vancomycin include: local pain, which may be severe and/or thrombophlebitis.
Damage to the kidneys and to the hearing were a side effect of the early impure versions of vancomycin, and these were prominent in the clinical trials conducted in the mid-1950s. Later trials using purer forms of vancomycin found that nephrotoxicity is an infrequent adverse effect (0.1–1% of patients), but that this is accentuated in the presence of aminoglycosides.
Rare adverse effects (<0.1% of patients) include: anaphylaxis, toxic epidermal necrolysis, erythema multiforme, red man syndrome (see below), superinfection, thrombocytopenia, neutropenia, leucopenia, tinnitus, dizziness and/or ototoxicity (see below).

Dosing considerations

Intravenous vs oral administration

Vancomycin needs to be given intravenously (IV) for systemic therapy since it doesn't cross through the intestinal lining. It is a large hydrophilic molecule which partitions poorly across the gastrointestinal mucosa. The only indication for oral vancomycin therapy is in the treatment of pseudomembranous colitis, where it must be given orally to reach the site of infection in the colon. Inhaled vancomycin has also been used (off-label), via nebulizer, for treatment of various infections of the upper and lower respiratory tract.

Red man syndrome

Vancomycin must be administered in a dilute solution slowly, over at least 60 minutes (maximum rate of 10 mg/minute for doses >500 mg).

Therapeutic drug monitoring

Vancomycin activity is considered to be time-dependent – that is, antimicrobial activity depends on the duration that the drug level exceeds the minimum inhibitory concentration (MIC) of the target organism. Thus, peak levels have not been shown to correlate with efficacy or toxicity – indeed concentration monitoring is unnecessary in most cases. Circumstances where therapeutic drug monitoring (TDM) is warranted include: patients receiving concomitant aminoglycoside therapy, patients with (potentially) altered pharmacokinetic parameters, patients on haemodialysis, during high dose or prolonged treatment, and patients with impaired renal function. In such cases, trough concentrations are measured.

Toxicity

Vancomycin has traditionally been considered a nephrotoxic and ototoxic drug, based on observations by early investigators of elevated serum levels in renally impaired patients who had experienced ototoxicity, and subsequently through case reports in the medical literature. However, as the use of vancomycin increased with the spread of MRSA beginning in the seventies, it was recognised that the previously reported rates of toxicity were not being observed. This was attributed to the removal of the impurities present in the earlier formulation of the drug, although those impurities were not specifically tested for toxicity. Most Lactobacillus species are also intrinsically resistant to vancomycin).
Most gram-negative bacteria are intrinsically resistant to vancomycin because of their outer membrane is impermeable to large glycopeptide molecules (with the exception of some non-gonococcal Neisseria species).

Acquired resistance

Acquired microbial resistance to vancomycin is a growing problem, particularly within health care facilities such as hospitals. With vancomycin being the last-line antibiotic for serious Gram-positive infections there's the growing prospect that resistance will result in a return to the days when fatal bacterial infections were common. Vancomycin-resistant enterococcus (VRE) emerged in 1987. Vancomycin resistance emerged in more common pathogenic organisms during the 1990s and 2000s, including vancomycin-intermediate Staphylococcus aureus (VISA), vancomycin-resistant Staphylococcus aureus (VRSA), and vancomycin-resistant Clostridium difficile. There is some suspicion that agricultural use of avoparcin, another similar glycopeptide antibiotic, has contributed to the emergence of vancomycin-resistant organisms.
One mechanism of resistance to vancomycin appears to be alteration to the terminal amino acid residues of the NAM/NAG-peptide subunits, normally D-alanyl-D-alanine, which vancomycin binds to. Variations such as D-alanyl-D-lactate and D-alanyl-D-serine result in only a 4-point hydrogen bonding interaction being possible between vancomycin and the peptide. This loss of just one point of interaction results in a 1000-fold decrease in affinity.
In Enterococci this modification appears to be due to the expression of an enzyme which alters the terminal residue. Three main resistance variants have been characterised to date among resistant Enterococcus faecium and E. faecalis populations.

VanA - resistance to vancomycin and teicoplanin, inducible on exposure to these agents

VanB - lower level resistance, inducible by vancomycin but strains may remain susceptible to teicoplanin

VanC - least clinically important, resistance only to vancomycin, constitutive resistance The development and use of novel antibiotics such as linezolid and daptomycin is expected to delay, but not halt, the emergence of bacteria resistant to all available antibiotics.

Further Information

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