Citizendia

Vancomycin
Systematic (IUPAC) name
unable to be assigned
Identifiers
CAS number1404-90-6
ATC codeA07AA09 J01XA01
PubChem14969
DrugBankAPRD01287
Chemical data
FormulaC66H75Cl2N9O24 
Mol. mass1449. IUPAC Nomenclature is a system of naming Chemical compounds and of describing the science of Chemistry in general CAS registry numbers are unique numerical identifiers for Chemical compounds Polymers biological sequences mixtures and Alloys They are also referred to The Anatomical Therapeutic Chemical Classification System is used for the classification of drugs It is controlled by the WHO Collaborating Centre for Drug ATC code A07 is a division of the Anatomical Therapeutic Chemical Classification System and part of the A Alimentary tract and metabolism section A section of the Anatomical Therapeutic Chemical Classification System. PubChem is a Database of chemical Molecules The system is maintained by the National Center for Biotechnology Information (NCBI a component The DrugBank database available at the University of Alberta is a unique Bioinformatics and Cheminformatics resource that combines detailed drug (i A chemical formula is a way of expressing information about the Atoms that constitute a particular Chemical compound, and how the relationship between those atoms changes Carbon (kɑɹbən is a Chemical element with the symbol C and its Atomic number is 6 Hydrogen (ˈhaɪdrədʒən is the Chemical element with Atomic number 1 Chlorine (ˈklɔriːn from the Greek word 'χλωρóς' ( khlôros, meaning 'pale green' is the Chemical element with Atomic number 17 and Nitrogen (ˈnaɪtɹəʤɪn is a Chemical element that has the symbol N and Atomic number 7 and Atomic weight 14 Oxygen (from the Greek roots ὀξύς (oxys (acid literally "sharp" from the taste of acids and -γενής (-genēs (producer literally begetteris the The molecular mass (abbreviated m of a substance, more commonly referred to as molecular weight and abbreviated as MW, is the Mass of one 3 g. mol-1
Pharmacokinetic data
BioavailabilityNegligible (oral)
MetabolismExcreted unchanged
Half life4–11 hours (adults)
6-10 days (adults, impaired renal function)
ExcretionRenal
Therapeutic considerations
Pregnancy cat.

B2 (Au), B (U.S.)

Legal status

S4 (Au), POM (UK), ℞-only (U. In Pharmacology, bioavailability is used to describe the fraction of an administered Dose of unchanged drug that reaches the Systemic circulation, one of Drug metabolism is the Metabolism of drugs, their Biochemical modification or degradation usually through specialized enzymatic systems The biological half-life of a substance is the time it takes for a substance (drug radioactive nuclide or other to lose half of its pharmacologic physiologic or radiologic activity Excretion is the process of eliminating waste products of Metabolism and other non-useful materials The pregnancy category of a pharmaceutical agent is an assessment of the risk of fetal injury due to the pharmaceutical if it is used as directed by the mother during For a topic outline on this subject see List of basic Australia topics. The United States of America —commonly referred to as the The regulation of therapeutic goods, that is drugs and therapeutic devices, varies by jurisdiction The United Kingdom of Great Britain and Northern Ireland, commonly known as the United Kingdom, the UK or Britain,is a Sovereign state located S. )

RoutesIV, oral
Crystal structure of a short peptide L-Lys-D-Ala-D-Ala (bacterial cell wall precursor, in green) bound to vancomycin (blue) through hydrogen bonds. Reported by Knox and Pratt in Antimicrob. Agents. Chemother., 1990 1342-1347
Crystal structure of a short peptide L-Lys-D-Ala-D-Ala (bacterial cell wall precursor, in green) bound to vancomycin (blue) through hydrogen bonds. In Pharmacology and Toxicology, a route Intravenous therapy or IV therapy is the giving of Liquid substances directly into a Vein. Reported by Knox and Pratt in Antimicrob. Agents. Chemother. , 1990 1342-1347

Vancomycin (INN) (pronounced /ˌvæŋkoʊˈmaɪsɪn/) is a glycopeptide antibiotic used in the prophylaxis and treatment of infections caused by Gram-positive bacteria. An International Nonproprietary Name ( INN; also known as rINN, for recommended International Nonproprietary Name or pINN for proposed Glycopeptide antibiotics are a class of Antibiotic drugs. The class is composed of a glycosylated cyclic or polycyclic Nonribosomal peptides In modern usage an antibiotic is a Chemotherapeutic agent with activity against Microorganisms such as Bacteria, fungi or Protozoa Prophylaxis ( Greek "προφυλάσσω" to guard or prevent beforehand) is any medical or Public health procedure whose purpose Gram-positive bacteria are those that are stained dark blue or violet by Gram staining. The Bacteria ( singular: bacterium) are a large group of unicellular Microorganisms Typically a few Micrometres in length bacteria have 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 is increasingly being displaced from this role by linezolid and the carbapenems. Drugs of last resort are drugs only used when all other options are exhausted Linezolid ( INN) (lɪˈnɛzəlɪd is a synthetic Antibiotic of the Oxazolidinone class used for the treatment of infections caused by multi-resistant Carbapenems are a class of Beta-lactam antibiotics with a broad spectrum of antibacterial activity and have a structure which renders them highly resistant to Beta-lactamases

Contents

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. Eli Lilly and Company ( is a global Pharmaceutical company and one of the world's largest corporations Borneo is the third largest island in the world and is located at the centre of Maritime Southeast Asia. The organism that produced it was eventually named Amycolatopsis orientalis. Amycolatopsis is a genus of High-GC content bacteria within the family Pseudonocardiaceae. [1] The original indication for vancomycin was for the treatment of penicillin-resistant Staphylococcus aureus. Penicillin (sometimes abbreviated PCN or pen) is a group of Beta-lactam antibiotics used in the treatment of Bacterial Infections Staphylococcus aureus (ˌstæfɨləˈkɒkəs ˈɔriəs literally "Golden Cluster Seed" and also known as golden staph) is the most common cause of [2][3]

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 did not 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. Penicillin (sometimes abbreviated PCN or pen) is a group of Beta-lactam antibiotics used in the treatment of Bacterial Infections Year 1958 ( MCMLVIII) was a Common year starting on Wednesday (link will display full calendar of the Gregorian calendar. Eli Lilly first marketed vancomycin hydrochloride under the trade name Vancocin. [2]

Vancomycin never became first line treatment for Staphylococcus aureus for several reasons:

  1. The drug must be given intravenously, because it is not absorbed orally. Intravenous therapy or IV therapy is the giving of Liquid substances directly into a Vein.
  2. β-lactamase-resistant semi-synthetic penicillins such as methicillin (and its successors, nafcillin and cloxacillin) were subsequently developed. Meticillin ( INN, BAN) or methicillin ( USAN) is a narrow spectrum Beta-lactam antibiotic of the Penicillin class Nafcillin sodium is a narrow spectrum Beta-lactam antibiotic of the Penicillin class Cloxacillin is a semisynthetic Antibiotic in the same class as Penicillin.
  3. Early trials using early impure forms of vancomycin ("Mississippi mud") which were found to be toxic to the ears and to the kidneys;[4] 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. Eli Lilly and Company ( is a global Pharmaceutical company and one of the world's largest corporations ViroPharma Incorporated, a Pharmaceutical company, develops and sells drugs that address serious diseases treated by physician specialists and in hospital settings 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. A patent is a set of Exclusive rights granted by a State to an inventor or his assignee for a fixed period of time in exchange for a disclosure of an The 1980s was the decade spanning from January 1 1980 to December 31 1989.

Biosynthesis

Figure 1: Modules and Domains of Vancomycin assembly.
Figure 1: Modules and Domains of Vancomycin assembly.

Vancomycin biosynthesis occurs via different nonribosomal protein synthases (NRPSs). [5] The enzymes determine the amino acid sequence during its assembly through its 7 modules. Enzymes are Biomolecules that catalyze ( ie increase the rates of Chemical reactions Almost all enzymes are Proteins Before Vancomycin is assembled through NRPS, the amino acids are first modified. In Chemistry, an amino acid is a Molecule containing both Amine and Carboxyl Functional groups In Biochemistry, this L-tyrosine is modified to become the β-hydroxychlorotyrosine (β-hTyr) and 4-hydroxyphenylglycine (HPG) residues. On the other hand, acetate is used to derive the 3,5 dihydroxyphenylglycine ring (3,5-DPG). [6]

Figure 2: Linear heptapeptide which consists of modified aromatic rings
Figure 2: Linear heptapeptide which consists of modified aromatic rings

Nonribosomal peptide synthesis occurs through distinct modules that can load and extend the protein by one amino acid through the amide bond formation at the contact sites of the activating domains. Proteins are large Organic compounds made of Amino acids arranged in a linear chain and joined together by Peptide bonds between the Carboxyl In Chemistry, an amide is one of three kinds of Compounds (sometimes called acid amide the organic Functional group characterized [7] Each module typically consists of an adenylation (A) domain, a peptidyl carrier protein (PCP) domain, and a condensation (C) or elongation domain. In the A domain, the specific amino acid is activated by converting into an aminoacyl adenylate enzyme complex attached to a 4’phosphopantetheine cofactor by thioesterification [8] [9] The complex is then transferred to the PCP domain with the expulsion of AMP. The PCP domain uses the attached 4’-phosphopantethein prosthetic group to load the growing peptide chain and their precursors. [10] The organization of the modules necessary to biosynthesize Vancomycin is shown in Figure 1. In the biosynthesis of Vancomycin, additional modification domains are present, such as the epimerization (E) domain, which is used isomerizes the amino acid from one stereochemistry to another, and a thioesterase domain (TE) is used as a catalyst for cyclization and releases of the molecule via a thioesterase scission. In Chemistry, epimers are Diastereomers that differ in configuration of only one stereogenic center Stereochemistry, a subdiscipline of Chemistry, involves the study of the relative spatial arrangement of Atoms within Molecules An important branch Thioesterases are enzymes which belong to the Esterase family

Figure 3: Modifications that are necessary for Vancomycin to become biologically active.
Figure 3: Modifications that are necessary for Vancomycin to become biologically active.

A set of multienzymes (peptide synthase CepA, CepB, and CepC) are responsible for assembling the heptapeptide. (Figure 2). The organization of CepA, CepB, and Cep C closely resembles orther peptide synthases such as those for surfactin (SrfA1, SrfA2 and SrfA3) and gramicidin (GrsA and GrsB). [7] Each peptide synthase activates codes for various amino acids in order to activate each domain. CepA codes for modules 1, 2 and 3, CepB codes for modules 4,5,and 6, and CepC codes for module 7 codes. The three peptide synthases are located at the start of the region of the bacterial genome linked with antibiotic biosynthesis and spans 27kb. In modern usage an antibiotic is a Chemotherapeutic agent with activity against Microorganisms such as Bacteria, fungi or Protozoa [7]

After the linear heptapeptide molecule is synthesized, Vancomycin has to further undergo post-translational modifications, such as oxidative cross-linking and glycosylation, in trans by distinct enzymes, referred to as tailoring enzymes, in order to become biologically active (Figure 3). Glycosylation is the enzymatic process that links Saccharides to produce glycans, either free or attached to Proteins and Lipids This enzymatic To convert the linear heptapeptide, eight enzymes, Open Reading Frames (ORF) 7, 8, 9, 10, 11, 14, 18, 20, and 21 are used. The enzymes ORF 7, 8,9 and 20 are P450 enzymes, ORF 10 and 18 show to nonheme haloperoxidases and ORF 9 and 14 are identified as putative hydroxylation enzymes. [11] With the help of these enzymes, β-hydroxyl groups are introduced onto tyrosine residues 2 and 6 and coupling occurs for rings 5 and 7, rings 4 and 6, and rings 4 and 2. Tyrosine (abbreviated as Tyr or Y) or 4-hydroxyphenylalanine, is one of the 20 Amino acids that are used by cells to synthesize In addition, a haloperoxidase is used to attach the chlorine atoms onto rings 2 and 6 via an oxidative process. [7]

Pharmacology and chemistry

It is a branched tricyclic glycosylated nonribosomal peptide produced by the fermentation of the Actinobacteria species Amycolatopsis orientalis (formerly designated Nocardia orientalis). Glycosylation is the enzymatic process that links Saccharides to produce glycans, either free or attached to Proteins and Lipids This enzymatic Nonribosomal peptide s (NRP are a class of Peptide Secondary metabolites, usually produced by Microorganisms like bacteria and Fungi Fermentation is the process of deriving energy from the oxidation of organic compounds such as carbohydrates using an endogenous electron acceptor which is Actinobacteria or actinomycetes are a group of Gram-positive bacteria with high G+C ratio. Amycolatopsis is a genus of High-GC content bacteria within the family Pseudonocardiaceae.

Vancomycin acts by inhibiting proper cell wall synthesis in Gram-positive bacteria. A cell wall is a tough flexible and sometimes fairly rigid layer surrounding a cell, located external to the Cell membrane, which provides the cell with structural The mechanism inhibited, and various factors related to entering the outer membrane of Gram-negative organisms mean that vancomycin is not active against Gram-negative bacteria (except some non-gonococcal species of Neisseria). Gram-negative bacteria are those Bacteria that do not retain Crystal violet dye in the Gram staining protocol Neisseria is a genus of Gram (- bacteria included among the Proteobacteria, a large group of Gram-negative forms

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. Not to be confused with Glycoprotein. Peptidoglycan, also known as murein, is a Polymer consisting of sugars and amino

The large hydrophilic molecule is able to form hydrogen bond interactions with the terminal D-alanyl-D-alanine moieties of the NAM/NAG-peptides. Hydrophile, from the Greek (hydros "water" and φιλια (philia "friendship" refers to a physical property of a Molecule A hydrogen bond results from a Dipole-dipole force between an Electronegative atom and a Hydrogen atom bonded to Nitrogen, Oxygen 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). Atropisomers are Stereoisomers resulting from hindered rotation about single bonds where the Steric strain barrier to rotation is high enough to allow for Alkane stereochemistry concerns the Stereochemistry of linear Alkanes and the linear alkane Conformers The existence of more than one conformation is due The form present in the drug is the thermodynamically more stable conformer, and, importantly, has more potent activity. In Chemistry, conformational isomerism is a form of Stereoisomerism in which Molecules with the same Structural formula (same connectivity

Vancomycin can be given orally, but this method is very expensive. It may also be used in treatment for clostridium difficile. Clostridium difficile (pronounced /klɒsˈtrɪdiəm dɪˈfɪsɪli/ also known as CDF/cdf' or 'C

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. Gram-positive bacteria are those that are stained dark blue or violet by Gram staining. In particular, vancomycin should not be used to treat methicillin-sensitive Staphylococcus aureus because it is inferior to penicillins such as nafcillin. Staphylococcus aureus (ˌstæfɨləˈkɒkəs ˈɔriəs literally "Golden Cluster Seed" and also known as golden staph) is the most common cause of Nafcillin sodium is a narrow spectrum Beta-lactam antibiotic of the Penicillin class [12][13]

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. Enterococcus is a Genus of Lactic acid bacteria of the phylum Firmicutes. The Centers for Disease Control and Prevention (or CDC) is an agency of the United States Department of Health and Human Services based in unincorporated These guidelines restrict use of vancomycin to the following indications:[14]

Adverse effects

Common adverse drug reactions (≥1% of patients) associated with IV vancomycin include: local pain, which may be severe and/or thrombophlebitis. Endocarditis is an Inflammation of the inner layer of the Heart, the Endocardium. Hypersensitivity (also called hypersensitivity reaction refers to undesirable (damaging discomfort-producing and sometimes fatal reactions produced by the normal immune system In Medicine, a prosthesis (plural prostheses) is an Artificial extension that replaces a missing Body part. An adverse drug reaction (abbreviated ADR) or adverse drug event (abbreviated ADE) is an expression that describes the unwanted negative consequences Thrombophlebitis is Phlebitis (vein Inflammation) related to a blood clot or Thrombus.

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. Nephrotoxicity (from Greek nephros "kidney" is a Poisonous effect of some substances both Toxic chemicals and Medication, on the Kidney 1–1% of patients), but that this is accentuated in the presence of aminoglycosides. An aminoglycoside is a molecule composed of a sugar group and an Amino group [15]

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). Anaphylaxis is an acute systemic (multi-system and severe Type I Hypersensitivity allergic reaction in humans and other Mammals Toxic epidermal necrolysis (TEN also known as Lyell's syndrome, is a life-threatening dermatological condition that is frequently induced by a reaction to medications Erythema multiforme is a skin condition of unknown etiology possibly mediated by deposition of Immune complex ( mostly IgM) in the superficial microvasculature of the Vancomycin ( INN) (ˌvæŋkoʊˈmaɪsɪn is a Glycopeptide Antibiotic used in the Prophylaxis and treatment of infections caused by In Virology, superinfection is the process by which a cell that has previously been infected by one Virus gets coinfected with another virus Thrombocytopenia (or -paenia, or thrombopenia in short is the presence of relatively few Platelets in Blood. Neutropenia (adjective neutropenic) from Latin Prefix neutro- and Greek Suffix -πενία (deficiency is Leukopenia (or leukocytopenia, or leucopenia, from Greek λευκό -white and πενία -deficiency is a decrease in the number of Tinnitus (tɪˈnaɪtəs or /ˈtɪnɪtəs/ from the Latin word for " Ringing " is the perception of sound within the human ear in the absence of corresponding Vancomycin ( INN) (ˌvæŋkoʊˈmaɪsɪn is a Glycopeptide Antibiotic used in the Prophylaxis and treatment of infections caused by [14]

Lately it has been emphasized that vancomycin can induce platelet-reactive antibodies in the patient, leading to severe thrombocytopenia and bleeding with florid petechial hemorrhages, ecchymoses, and wet purpura. Thrombocytopenia (or -paenia, or thrombopenia in short is the presence of relatively few Platelets in Blood. [16]

Dosing considerations

Intravenous vs oral administration

Vancomycin needs to be given intravenously (IV) for systemic therapy since it does not cross through the intestinal lining. Intravenous therapy or IV therapy is the giving of Liquid substances directly into a Vein. It is a large hydrophilic molecule which partitions poorly across the gastrointestinal mucosa. The mucous membranes (or mucosae; singular mucosa) are linings of mostly endodermal origin covered in Epithelium, which are involved in 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. Clostridium difficile Pseudomembranous colitis is an infection of the colon often but not always caused by the Bacterium Clostridium difficile Inhaled vancomycin has also been used (off-label), via nebulizer, for treatment of various infections of the upper and lower respiratory tract. Off-label use is the practice of prescribing drugs for a purpose outside the scope of the drug's approved label most often concerning the drug's indication. In Medicine, a nebulizer is a device used to administer medication to people in the form of a mist inhaled into the lungs

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). [14] This is due to the high incidence of pain and thrombophlebitis and to avoid an infusion reaction known as the red man syndrome or red neck syndrome. Pain, in the sense of physical pain, is a typical sensory experience that may be described as the unpleasant awareness of a noxious stimulus or bodily harm Thrombophlebitis is Phlebitis (vein Inflammation) related to a blood clot or Thrombus. This syndrome, usually appearing within 4–10 minutes after the commencement or soon after the completion of an infusion, is characterised by flushing and/or and an erythematous rash that affects the face, neck and upper torso. Erythema is redness of the Skin caused by Capillary congestion Less frequently, hypotension and angioedema may also occur. In Physiology and Medicine, hypotension refers to an abnormally low Blood pressure. Angioedema ( BE: angiooedema) also known by its Eponym Quincke's edema, is the rapid swelling ( Edema) of the Dermis Symptoms may be treated with antihistamines, including diphenhydramine. A histamine antagonist is an agent which serves to inhibit the release or action of Histamine. Pharmacological action Diphenhydramine (dye fen hye' dra meen works by blocking the effect of histamine at H1 receptor sites [17]

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. Minimum inhibitory concentration ( MIC) in Microbiology, is the lowest Concentration of an Antimicrobial that will inhibit the visible growth 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. Therapeutic drug monitoring is a branch of Clinical chemistry that specializes in the measurement of Medication levels in Blood. Pharmacokinetics (in Greek: “pharmacon” meaning drug and “kinetikos” meaning putting in motion the study of time dependency sometimes abbreviated as “PK” is a In Medicine, hemodialysis (also haemodialysis) is a method for removing waste products such as Potassium and Urea, as well as free water In such cases, trough concentrations are measured. [14][18][19][20]

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. Nephrotoxicity (from Greek nephros "kidney" is a Poisonous effect of some substances both Toxic chemicals and Medication, on the Kidney Ototoxicity is damage of the Ear ( oto) specifically the Cochlea or auditory nerve and sometimes the Vestibulum, by a Toxin 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. [3]

Nephrotoxicity

Subsequent reviews of accumulated case reports of vancomycin-related nephrotoxicity found that many of the patients had also received other known nephrotoxins, particularly aminoglycosides. Nephrotoxicity (from Greek nephros "kidney" is a Poisonous effect of some substances both Toxic chemicals and Medication, on the Kidney An aminoglycoside is a molecule composed of a sugar group and an Amino group Most of the rest had other confounding factors, or insufficient data regarding the possibility of such, that prohibited the clear association of vancomycin with the observed renal dysfunction.

In 1994, Cantu and colleagues found that the use of vancomycin monotherapy was clearly documented in only three of 82 available cases in the literature. [18] Prospective and retrospective studies attempting to evaluate the incidence of vancomycin-related nephrotoxicity have largely been methodologically flawed and have produced variable results. The most methodologically sound investigations indicate that the actual incidence of vancomycin-induced nephrotoxicity is around 5–7%. To put this into context, similar rates of renal dysfunction have been reported for cefamandole and benzylpenicillin, two reputedly non-nephrotoxic antibiotics. Cefamandole ( INN, also known as cephamandole) is a broad-spectrum Cephalosporin Antibiotic. Penicillin (sometimes abbreviated PCN or pen) is a group of Beta-lactam antibiotics used in the treatment of Bacterial Infections

Additionally, evidence to relate nephrotoxicity to vancomycin serum levels is inconsistent. Some studies have indicated an increased rate of nephrotoxicity when trough levels exceed 10 µg/mL, but others have not reproduced these results. Nephrotoxicity has also been observed with concentrations within the "therapeutic" range as well. Essentially, the reputation of vancomycin as a nephrotoxin is over-stated, and it has not been demonstrated that maintaining vancomycin serum levels within certain ranges will prevent its nephrotoxic effects, when they do occur.

Ototoxicity

Attempts to establish rates of vancomycin-induced ototoxicity are even more difficult due to the scarcity of quality evidence. The current consensus is that clearly related cases of vancomycin ototoxicity are rare. The association between vancomycin serum levels and ototoxicity is also uncertain. While cases of ototoxicity have been reported in patients whose vancomycin serum level exceeded 80 µg/mL, cases have been reported in patients with therapeutic levels as well. Thus, it also remains unproven that therapeutic drug monitoring of vancomycin for the purpose of maintaining "therapeutic" levels will prevent ototoxicity. Therapeutic drug monitoring is a branch of Clinical chemistry that specializes in the measurement of Medication levels in Blood.

Interactions with other nephrotoxins

Another area of controversy and uncertainty concerns the question of whether, and if so, to what extent, vancomycin increases the toxicity of other nephrotoxins. Clinical studies have yielded variable results, but animal models indicate that there probably is some increased nephrotoxic effect when vancomycin is added to nephrotoxins such as aminoglycosides. However, a dose- or serum level-effect relationship has not been established.

Antibiotic resistance

Intrinsic resistance

There are a few gram-positive bacteria that are intrinsically resistant to vancomycin: these are Leuconostoc and Pediococcus species, but these organisms are rare causes of disease in humans. Gram-positive bacteria are those that are stained dark blue or violet by Gram staining. Leuconostoc is a genus of Gram-positive bacteria, placed within the family of Leuconostocaceae. Pediococcus is a genus of Gram-positive Lactic acid bacteria, placed within the family of Lactobacillaceae. [21] Most Lactobacillus species are also intrinsically resistant to vancomycin[21] (the exception is the finding of a few strains (but not all) of L. acidophilus[22]). Lactobacillus is a Genus of Gram-positive Facultative anaerobic or Microaerophilic Bacteria. Lactobacillus acidophilus is one Species in the genus Lactobacillus.

Most gram-negative bacteria are intrinsically resistant to vancomycin because of their outer membrane is impermeable to large glycopeptide molecules[23] (with the exception of some non-gonococcal Neisseria species). Gram-negative bacteria are those Bacteria that do not retain Crystal violet dye in the Gram staining protocol Neisseria is a genus of Gram (- bacteria included among the Proteobacteria, a large group of Gram-negative forms [24]

Acquired resistance

Acquired microbial resistance to vancomycin is a growing problem, particularly within health care facilities such as hospitals. Antibiotic resistance is the ability of a Microorganism to withstand the effects of Antibiotics. With vancomycin being the last-line antibiotic for serious Gram-positive infections there is the growing prospect that resistance will result in a return to the days when fatal bacterial infections were common. Gram-positive bacteria are those that are stained dark blue or violet by Gram staining. Vancomycin-resistant enterococcus (VRE) emerged in 1987. Vancomycin-resistant enterococcus (VRE is the name given to a group of bacterial species of the genus Enterococcus that is resistant Year 1987 ( MCMLXXXVII) was a Common year starting on Thursday (link displays 1987 Gregorian calendar) 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. The 1990s collectively refers to the years between and including 1990 and 1999 Vancomycin-resistant Staphylococcus aureus (VRSA is a strain of Staphylococcus aureus that has become resistant to the Glycopeptide antibiotic Vancomycin-resistant Staphylococcus aureus (VRSA is a strain of Staphylococcus aureus that has become resistant to the Glycopeptide antibiotic Clostridium difficile (pronounced /klɒsˈtrɪdiəm dɪˈfɪsɪli/ also known as CDF/cdf' or 'C [25][26] 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. In Chemistry, an amino acid is a Molecule containing both Amine and Carboxyl Functional groups In Biochemistry, this 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.

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. Teicoplanin is an Antibiotic used in the Prophylaxis and treatment of serious infections caused by Gram-positive bacteria, including methicillin-resistant Linezolid ( INN) (lɪˈnɛzəlɪd is a synthetic Antibiotic of the Oxazolidinone class used for the treatment of infections caused by multi-resistant Daptomycin is a novel Lipopeptide Antibiotic used in the treatment of certain infections caused by Gram-positive organisms

References

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  2. ^ a b Moellering, RC Jr. (2006). "Vancomycin: A 50-Year Reassessment". Clin Infect Dis 42: S3–S4. PMID 16323117.  
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  4. ^ Griffith RS. (1981). "Introduction to vancomycin". Rev Infect Dis 3: S2004.  
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See also

External links

Drug resistance is the reduction in effectiveness of a drug in curing a disease or improving a patient's symptoms Antibiotic resistance is the ability of a Microorganism to withstand the effects of Antibiotics. Vancomycin-resistant Staphylococcus aureus (VRSA is a strain of Staphylococcus aureus that has become resistant to the Glycopeptide antibiotic Vancomycin-resistant enterococcus (VRE is the name given to a group of bacterial species of the genus Enterococcus that is resistant

Dictionary

vancomycin

-noun

  1. (medicine) A glycopeptide antibiotic, produced by the actinomycete Amycolaptosis orientalis, used against Gram-positive bacteria, especially staphylococci and enterococci.
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