Vancomycin
Encyclopedia
Vancomycin INN
(icon) 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 is increasingly being displaced from this role by linezolid
(Zyvox) available PO and IV and daptomycin
(Cubicin) IV and quinupristin/dalfopristin
(Synercid) IV.
(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 called compound 05865, but was eventually given the generic name vancomycin, derived from the term "vanquish". One advantage that was quickly apparent is 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's being fast-tracked for approval by the FDA
in 1958. Eli Lilly first marketed vancomycin hydrochloride under the trade name Vancocin and as COVANC from Nucleus, India.
Vancomycin never became the first-line treatment for Staphylococcus aureus for several reasons:
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; the FDA has authorized the sale of several generic versions in the USA, including from manufacturers Bioniche Pharma, Baxter Healthcare, Sandoz
, Akorn Strides and Hospira
.
An oral form of vancomycin was originally approved by the FDA in 1986 for the treatment of Clostridium difficile
induced pseudomembranous colitis
. It is not orally absorbed into the blood and remains in the gastrointestinal tract to eradicate C. difficle. This product is currently marketed by ViroPharma
in the USA.
Vancomycin biosynthesis occurs via different nonribosomal protein synthases (NRPSs). The enzymes determine the amino acid sequence during its assembly through its 7 modules. Before Vancomycin is assembled through NRPS, the amino acids are first modified. 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).
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. 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 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. 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 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.
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 other peptide synthases such as those for surfactin (SrfA1, SrfA2, and SrfA3) and gramicidin (GrsA and GrsB). 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. The three peptide synthases are located at the start of the region of the bacterial genome linked with antibiotic
biosynthesis and spans 27 kb.
After the linear heptapeptide molecule is synthesized, Vancomycin has to undergo further 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). To convert the linear heptapeptide, eight enzymes, open reading frame
s (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. 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. In addition, a haloperoxidase is used to attach the chlorine atoms onto rings 2 and 6 via an oxidative process.
nonribosomal peptide
produced by the fermentation
of the Actinobacteria
species Amycolatopsis orientalis
(formerly designated Nocardia orientalis).
Vancomycin exhibits atropisomer
ism — it has multiple chemically distinct rotamers owing to the rotational restriction of some of the bonds. The form present in the drug is the thermodynamically more stable conformer and, therefore, has more potent activity.
synthesis in Gram-positive bacteria. Due to the different mechanism by which Gram-negative bacteria produce their cell walls and the various factors related to entering the outer membrane of Gram-negative
organisms, vancomycin is not active against Gram-negative bacteria (except some non-gonococcal species of Neisseria
).
The large hydrophilic molecule is able to form hydrogen bond
interactions with the terminal D-alanyl-D-alanine moieties of the NAM/NAG-peptides. Under normal circumstances, this is a five-point interaction. This binding of vancomycin to the D-Ala-D-Ala prevents cell wall synthesis in two ways. It prevents the synthesis of the long polymers of N-acetylmuramic acid (NAM) and N-acetylglucosamine (NAG) that form the backbone strands of the bacterial cell wall, and it prevents the backbone polymers that do manage to form from cross-linking with each other.
bacteria that are unresponsive to other less-toxic antibiotics. In particular, vancomycin should not be used to treat methicillin-sensitive Staphylococcus aureus
because it is 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:
Common adverse drug reaction
s (≥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 aminoglycoside
s.
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).
It has recently 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.
, where it must be given orally to reach the site of infection in the colon. Following oral administration, the fecal concentration of vancomycin is around 500 µg/mL (sensitive strains of C. difficile have a mean inhibitory concentration of ≤2 µg/mL)
Inhaled vancomycin has also been used (off-label), via nebulizer
, for treatment of various infections of the upper and lower respiratory tract.
The caustic nature of vancomycin makes IV therapy using peripheral lines a risk for thrombophlebitis. Ideally, central lines, PICCs, or infusion ports should be used.
and thrombophlebitis
and to avoid an infusion reaction known as the red man syndrome or red neck syndrome. This syndrome, usually appearing within 4–10 minutes after the commencement or soon after the completion of an infusion, is characterized by flushing and/or an erythematous rash that affects the face, neck, and upper torso. These findings are due to non-specific mast cell
degranulation and are not an IgE
-mediated allergic reaction. Less frequently, hypotension
and angioedema
may also occur. Symptoms may be treated or prevented with antihistamine
s, including diphenhydramine
, and are less likely to occur with slow infusion.
(MIC) of the target organism. Thus, peak serum levels have not been shown to correlate with efficacy or toxicity – indeed concentration monitoring is unnecessary in most cases. Circumstances in which therapeutic drug monitoring
(TDM) is warranted include: patients receiving concomitant aminoglycoside therapy, patients with (potentially) altered pharmacokinetic
parameters, patients on haemodialysis
, patients administered high-dose or prolonged treatment, and patients with impaired renal function. In such cases, trough concentrations are measured.
Target ranges for serum vancomycin concentrations have changed over the years. Early authors suggested peak levels of 30–40 mg/L and trough levels
of 5–10 mg/L,
but current recommendations are that peak levels need not be measured and that trough levels
of 10-15 or 15–20 mg/L, depending on the nature of the infection and the specific needs of the patient, may be appropriate.
found that many of the patients had also received other known nephrotoxins, in particular, aminoglycosides. 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. 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.
In addition, 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. In essence, 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.
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.
bacteria that are intrinsically resistant to vancomycin: Leuconostoc
and Pediococcus
species, but these organisms are rare causes of disease in humans. Most Lactobacillus
species are also intrinsically resistant to vancomycin (the exception is the finding of a few strains (but not all) of L. acidophilus
).
Most gram-negative
bacteria are intrinsically resistant to vancomycin because their outer membrane is impermeable to large glycopeptide molecules (with the exception of some non-gonococcal Neisseria
species).
to vancomycin is a growing problem, in particular, within healthcare facilities such as hospitals. While newer alternatives to vancomycin exist, such as Linezolid
(2000) and daptomycin
(2003), the widespread use of vancomycin makes resistance to the drug a significant worry, especially for individual patients if resistant infections are not quickly identified and the patient continues the ineffective treatment. 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) and vancomycin-resistant Staphylococcus aureus
(VRSA). 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 involves the alteration to the terminal amino acid residues of the NAM/NAG-peptide subunits, under normal conditions, D-alanyl-D-alanine, to which vancomycin binds. The D-alanyl-D-lactate variation results in the loss of one hydrogen-bonding interaction (4, as opposed to 5 for D-alanyl-D-alanine) possible between vancomycin and the peptide. This loss of just one point of interaction results in a 1000-fold decrease in affinity. The D-alanyl-D-serine variation causes a six-fold loss of affinity between vancomycin and the peptide, likely due to steric hindrance.
In enterococci, this modification appears to be due to the expression of an enzyme that alters the terminal residue. Three main resistance variants have been characterised to date among resistant Enterococcus faecium and E. faecalis populations.
2011: A variant of vancomycin has been tested that binds to the lactate variation and also binds well to the original target, thus reinstates potent antimicrobial activity.
International Nonproprietary Name
An International Nonproprietary Name is the official nonproprietary or generic name given to a pharmaceutical substance, as designated by the World Health Organization...
(icon) is a glycopeptide antibiotic
Glycopeptide antibiotic
Glycopeptide antibiotics are a class of antibiotic drugs. The class is composed of glycosylated cyclic or polycyclic nonribosomal peptides. Significant glycopeptide antibiotics include vancomycin, teicoplanin, telavancin, bleomycin, ramoplanin, and decaplanin....
used in the prophylaxis and treatment of infections caused by Gram-positive
Gram-positive
Gram-positive bacteria are those that are stained dark blue or violet by Gram staining. This is in contrast to Gram-negative bacteria, which cannot retain the crystal violet stain, instead taking up the counterstain and appearing red or pink...
bacteria
Bacteria
Bacteria are a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria have a wide range of shapes, ranging from spheres to rods and spirals...
. It has traditionally been reserved as a drug of "last resort"
Drug of last resort
Drugs of last resort are drugs only used when all other options are exhausted. Many of the best known are antibiotics, antivirals, or chemotherapy agents. In those cases, they have the most potent antibiotic, antiviral, or anticancer effects, and/or are drugs for which no resistant strains are...
, 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
Linezolid
Linezolid is a synthetic antibiotic used for the treatment of serious infections caused by Gram-positive bacteria that are resistant to several other antibiotics...
(Zyvox) available PO and IV and daptomycin
Daptomycin
Daptomycin is a novel lipopeptide antibiotic used in the treatment of certain infections caused by Gram-positive organisms. It is a naturally occurring compound found in the soil saprotroph Streptomyces roseosporus. Its distinct mechanism of action means that it may be useful in treating infections...
(Cubicin) IV and quinupristin/dalfopristin
Quinupristin/dalfopristin
Quinupristin/dalfopristin is a combination of two antibiotics used to treat infections by staphylococci and by vancomycin-resistant Enterococcus faecium....
(Synercid) IV.
History
Vancomycin was first isolated in 1953 by Edmund KornfeldEdmund Kornfeld
Edmund Carl Kornfeld is an American Organic Chemist who devoted his life to the research of new drugs. His leading discovery, with the help of a team, was a unique compound that was designated as 05865, which was later known as Vancomycin. Edmund Kornfeld received his PhD in chemistry from Harvard...
(working at Eli Lilly
Eli Lilly and Company
Eli Lilly and Company is a global pharmaceutical company. Eli Lilly's global headquarters is located in Indianapolis, Indiana, in the United States...
) from a soil sample collected from the interior jungles of Borneo
Borneo
Borneo is the third largest island in the world and is located north of Java Island, Indonesia, at the geographic centre of Maritime Southeast Asia....
by a missionary. The organism that produced it was eventually named Amycolatopsis orientalis. The original indication for vancomycin was for the treatment of penicillin
Penicillin
Penicillin is a group of antibiotics derived from Penicillium fungi. They include penicillin G, procaine penicillin, benzathine penicillin, and penicillin V....
-resistant Staphylococcus aureus
Staphylococcus aureus
Staphylococcus aureus is a facultative anaerobic Gram-positive coccal bacterium. It is frequently found as part of the normal skin flora on the skin and nasal passages. It is estimated that 20% of the human population are long-term carriers of S. aureus. S. aureus is the most common species of...
.
The compound was initially called compound 05865, but was eventually given the generic name vancomycin, derived from the term "vanquish". One advantage that was quickly apparent is that staphylococci did not develop significant resistance despite serial passage in culture media containing vancomycin. The rapid development of penicillin
Penicillin
Penicillin is a group of antibiotics derived from Penicillium fungi. They include penicillin G, procaine penicillin, benzathine penicillin, and penicillin V....
resistance by staphylococci led to the compound's being fast-tracked for approval by the FDA
Food and Drug Administration
The Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments...
in 1958. Eli Lilly first marketed vancomycin hydrochloride under the trade name Vancocin and as COVANC from Nucleus, India.
Vancomycin never became the first-line treatment for Staphylococcus aureus for several reasons:
- It possesses poor oral bioavailability; it must be given intravenously for most infections.
- β-Lactamase-resistant semi-synthetic penicillins such as methicillinMethicillinMeticillin or methicillin is a narrow-spectrum beta-lactam antibiotic of the penicillin class. It should not be confused with the antibiotic metacycline.-History:Methicillin was developed by Beecham in 1959...
(and its successors, nafcillin and cloxacillinCloxacillinCloxacillin is a semisynthetic antibiotic in the same class as penicillin. Cloxacillin was discovered and developed by Beecham. It is sold under a number of trade names, including Cloxapen, Cloxacap, Tegopen and Orbenin....
) were subsequently developed, which have better activity against non-MRSA staphylococci. - Early trials used early impure forms of vancomycin ("Mississippi mud"), which were found to be toxic to the ears and to the kidneys; these findings led to vancomycin's being relegated to the position of a drug of last resort.
In 2004, Eli Lilly
Eli Lilly and Company
Eli Lilly and Company is a global pharmaceutical company. Eli Lilly's global headquarters is located in Indianapolis, Indiana, in the United States...
licensed Vancocin to ViroPharma
ViroPharma
ViroPharma Incorporated, a pharmaceutical company, develops and sells drugs that address serious diseases treated by physician specialists and in hospital settings...
in the U.S., Flynn Pharma in the UK, and Aspen Pharmacare in Australia. The patent
Patent
A patent is a form of intellectual property. It consists of a set of exclusive rights granted by a sovereign state to an inventor or their assignee for a limited period of time in exchange for the public disclosure of an invention....
expired in the early 1980s; the FDA has authorized the sale of several generic versions in the USA, including from manufacturers Bioniche Pharma, Baxter Healthcare, Sandoz
Sandoz
Founded in 2003, Sandoz presently is the generic drug subsidiary of Novartis, a multinational pharmaceutical company. The company develops, manufactures and markets generic drugs as well as pharmaceutical and biotechnological active ingredients....
, Akorn Strides and Hospira
Hospira
Hospira, Inc. is a U.S.-based global pharmaceutical and medical device company with headquarters in Lake Forest, Illinois. It has approximately 14,000 employees. Hospira is the world's largest producer of generic injectable pharmaceuticals, manufacturing generic acute-care and oncology...
.
An oral form of vancomycin was originally approved by the FDA in 1986 for the treatment of Clostridium difficile
Clostridium difficile
Clostridium difficile , also known as "CDF/cdf", or "C...
induced pseudomembranous colitis
Pseudomembranous colitis
Pseudomembranous colitis, a cause of antibiotic-associated diarrhea , is an infection of the colon. It is often, but not always, caused by the bacterium Clostridium difficile. Because of this, the informal name C. difficile colitis is also commonly used. The illness is characterized by...
. It is not orally absorbed into the blood and remains in the gastrointestinal tract to eradicate C. difficle. This product is currently marketed by ViroPharma
ViroPharma
ViroPharma Incorporated, a pharmaceutical company, develops and sells drugs that address serious diseases treated by physician specialists and in hospital settings...
in the USA.
Biosynthesis
Protein domain
A protein domain is a part of protein sequence and structure that can evolve, function, and exist independently of the rest of the protein chain. Each domain forms a compact three-dimensional structure and often can be independently stable and folded. Many proteins consist of several structural...
that can load and extend the protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
by one amino acid through the amide
Amide
In chemistry, an amide is an organic compound that contains the functional group consisting of a carbonyl group linked to a nitrogen atom . The term refers both to a class of compounds and a functional group within those compounds. The term amide also refers to deprotonated form of ammonia or an...
bond formation at the contact sites of the activating domains. 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 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. 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 isomerizes the amino acid from one stereochemistry
Stereochemistry
Stereochemistry, a subdiscipline of chemistry, involves the study of the relative spatial arrangement of atoms within molecules. An important branch of stereochemistry is the study of chiral molecules....
to another, and a thioesterase domain (TE) is used as a catalyst for cyclization and releases of the molecule via a thioesterase
Thioesterase
Thioesterases are enzymes which belong to the Esterase family. Esterases, in turn, are one type of the several hydrolases known.Thioesterases exhibit Esterase activity specifically at a thiol group.Thioesterases or thiolester hydrolases are identified as members of E.C.3.1.2.-Examples:Acetyl-coA...
scission.
Antibiotic
An antibacterial is a compound or substance that kills or slows down the growth of bacteria.The term is often used synonymously with the term antibiotic; today, however, with increased knowledge of the causative agents of various infectious diseases, antibiotic has come to denote a broader range of...
biosynthesis and spans 27 kb.
After the linear heptapeptide molecule is synthesized, Vancomycin has to undergo further modifications, such as oxidative cross-linking and glycosylation
Glycosylation
Glycosylation is the reaction in which a carbohydrate, i.e. a glycosyl donor, is attached to a hydroxyl or other functional group of another molecule . In biology glycosylation refers to the enzymatic process that attaches glycans to proteins, lipids, or other organic molecules...
, in trans by distinct enzymes, referred to as tailoring enzymes, in order to become biologically active (Figure 3). To convert the linear heptapeptide, eight enzymes, open reading frame
Open reading frame
In molecular genetics, an open reading frame is a DNA sequence that does not contain a stop codon in a given reading frame.Normally, inserts which interrupt the reading frame of a subsequent region after the start codon cause frameshift mutation of the sequence and dislocate the sequences for stop...
s (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. With the help of these enzymes, β-hydroxyl groups are introduced onto tyrosine
Tyrosine
Tyrosine or 4-hydroxyphenylalanine, is one of the 22 amino acids that are used by cells to synthesize proteins. Its codons are UAC and UAU. It is a non-essential amino acid with a polar side group...
residues 2 and 6, and coupling occurs for rings 5 and 7, rings 4 and 6, and rings 4 and 2. In addition, a haloperoxidase is used to attach the chlorine atoms onto rings 2 and 6 via an oxidative process.
Pharmacology and chemistry
Vancomycin is a branched tricyclic glycosylatedGlycosylation
Glycosylation is the reaction in which a carbohydrate, i.e. a glycosyl donor, is attached to a hydroxyl or other functional group of another molecule . In biology glycosylation refers to the enzymatic process that attaches glycans to proteins, lipids, or other organic molecules...
nonribosomal peptide
Nonribosomal peptide
Nonribosomal peptides are a class of peptide secondary metabolites, usually produced by microorganisms like bacteria and fungi. Nonribosomal peptides are also found in higher organisms, such as nudibranchs, but are thought to be made by bacteria inside these organisms...
produced by the fermentation
Fermentation (biochemistry)
Fermentation is the process of extracting energy from the oxidation of organic compounds, such as carbohydrates, using an endogenous electron acceptor, which is usually an organic compound. In contrast, respiration is where electrons are donated to an exogenous electron acceptor, such as oxygen,...
of the Actinobacteria
Actinobacteria
Actinobacteria are a group of Gram-positive bacteria with high guanine and cytosine content. They can be terrestrial or aquatic. Actinobacteria is one of the dominant phyla of the bacteria....
species Amycolatopsis orientalis
Amycolatopsis
Amycolatopsis is a genus of high-GC content bacteria within the family Pseudonocardiaceae.These produce Epoxyquinomicin C, a weak antibiotic and anti-inflammatory agent....
(formerly designated Nocardia orientalis).
Vancomycin exhibits atropisomer
Atropisomer
Atropisomers are stereoisomers resulting from hindered rotation about single bonds where the steric strain barrier to rotation is high enough to allow for the isolation of the conformers. The word atropisomer is derived from the Greek a, meaning not, and tropos, meaning turn...
ism — it has multiple chemically distinct rotamers owing to the rotational restriction of some of the bonds. The form present in the drug is the thermodynamically more stable conformer and, therefore, has more potent activity.
Mechanism of Action
Vancomycin acts by inhibiting proper cell wallCell wall
The cell wall is the tough, usually flexible but sometimes fairly rigid layer that surrounds some types of cells. It is located outside the cell membrane and provides these cells with structural support and protection, and also acts as a filtering mechanism. A major function of the cell wall is to...
synthesis in Gram-positive bacteria. Due to the different mechanism by which Gram-negative bacteria produce their cell walls and the various factors related to entering the outer membrane of Gram-negative
Gram-negative
Gram-negative bacteria are bacteria that do not retain crystal violet dye in the Gram staining protocol. In a Gram stain test, a counterstain is added after the crystal violet, coloring all Gram-negative bacteria with a red or pink color...
organisms, vancomycin is not active against Gram-negative bacteria (except some non-gonococcal species of Neisseria
Neisseria
The Neisseria is a large genus of commensal bacteria that colonize the mucosal surfaces of many animals. Of the 11 species that colonize humans, only two are pathogens. N. meningitidis and N. gonorrhoeae often cause asymptomatic infections, a commensal-like behavior...
).
The large hydrophilic molecule is able to form hydrogen bond
Hydrogen bond
A hydrogen bond is the attractive interaction of a hydrogen atom with an electronegative atom, such as nitrogen, oxygen or fluorine, that comes from another molecule or chemical group. The hydrogen must be covalently bonded to another electronegative atom to create the bond...
interactions with the terminal D-alanyl-D-alanine moieties of the NAM/NAG-peptides. Under normal circumstances, this is a five-point interaction. This binding of vancomycin to the D-Ala-D-Ala prevents cell wall synthesis in two ways. It prevents the synthesis of the long polymers of N-acetylmuramic acid (NAM) and N-acetylglucosamine (NAG) that form the backbone strands of the bacterial cell wall, and it prevents the backbone polymers that do manage to form from cross-linking with each other.
Indications
Vancomycin is indicated for the treatment of serious, life-threatening infections by Gram-positiveGram-positive
Gram-positive bacteria are those that are stained dark blue or violet by Gram staining. This is in contrast to Gram-negative bacteria, which cannot retain the crystal violet stain, instead taking up the counterstain and appearing red or pink...
bacteria that are unresponsive to other less-toxic antibiotics. In particular, vancomycin should not be used to treat methicillin-sensitive Staphylococcus aureus
Staphylococcus aureus
Staphylococcus aureus is a facultative anaerobic Gram-positive coccal bacterium. It is frequently found as part of the normal skin flora on the skin and nasal passages. It is estimated that 20% of the human population are long-term carriers of S. aureus. S. aureus is the most common species of...
because it is inferior to penicillins such as nafcillin.
The increasing emergence of vancomycin-resistant enterococci
Enterococcus
Enterococcus is a genus of lactic acid bacteria of the phylum Firmicutes. Enterococci are Gram-positive cocci that often occur in pairs or short chains, and are difficult to distinguish from streptococci on physical characteristics alone. Two species are common commensal organisms in the...
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 penicillinPenicillinPenicillin is a group of antibiotics derived from Penicillium fungi. They include penicillin G, procaine penicillin, benzathine penicillin, and penicillin V....
s (methicillin-resistant Staphylococcus aureusMethicillin-resistant Staphylococcus aureusMethicillin-resistant Staphylococcus aureus is a bacterium responsible for several difficult-to-treat infections in humans. It is also called multidrug-resistant Staphylococcus aureus and oxacillin-resistant Staphylococcus aureus...
and multi-resistant Staphylococcus epidermidisStaphylococcus epidermidisStaphylococcus epidermidis is one of thirty-three known species belonging to the genus Staphylococcus. It is part of human skin flora, and consequently part of human flora. It can also be found in the mucous membranes and in animals. Due to contamination, it is probably the most common species...
(MRSE)) or in individuals with serious allergy to penicillinPenicillinPenicillin is a group of antibiotics derived from Penicillium fungi. They include penicillin G, procaine penicillin, benzathine penicillin, and penicillin V....
s - Treatment of Pseudomembranous colitisPseudomembranous colitisPseudomembranous colitis, a cause of antibiotic-associated diarrhea , is an infection of the colon. It is often, but not always, caused by the bacterium Clostridium difficile. Because of this, the informal name C. difficile colitis is also commonly used. The illness is characterized by...
caused by the bacterium Clostridium difficileClostridium difficileClostridium difficile , also known as "CDF/cdf", or "C...
; in particular, in cases of relapse or where the infection is unresponsive to metronidazoleMetronidazoleMetronidazole is a nitroimidazole antibiotic medication used particularly for anaerobic bacteria and protozoa. Metronidazole is an antibiotic, amebicide, and antiprotozoal....
treatment (for this indication, vancomycin is given orally, rather than via its typical, I.V. route) - For treatment of infections caused by gram-positive microorganisms in patients with serious allergies to beta-lactam antimicrobials.
- Antibacterial prophylaxis for endocarditisEndocarditisEndocarditis is an inflammation of the inner layer of the heart, the endocardium. It usually involves the heart valves . Other structures that may be involved include the interventricular septum, the chordae tendineae, the mural endocardium, or even on intracardiac devices...
following certain procedures in penicillin-hypersensitiveHypersensitivityHypersensitivity refers to undesirable reactions produced by the normal immune system, including allergies and autoimmunity. These reactions may be damaging, uncomfortable, or occasionally fatal. Hypersensitivity reactions require a pre-sensitized state of the host. The four-group classification...
individuals at high risk - Surgical prophylaxis for major procedures involving implantation of prosthesesProsthesisIn medicine, a prosthesis, prosthetic, or prosthetic limb is an artificial device extension that replaces a missing body part. It is part of the field of biomechatronics, the science of using mechanical devices with human muscle, skeleton, and nervous systems to assist or enhance motor control...
in institutions with a high rate of MRSA or MRSE - Early in treatment as an empiric antibiotic to cover for possible MRSA infection while waiting for culture identification of the infecting organism.
Adverse effects
Although vancomycin levels are usually monitored, in an effort to reduce adverse events, the value of this is not beyond debate. Peak and trough levels are usually monitored, and, for research purposes, the area under the curve is also sometimes used. Toxicity is best monitored by looking at trough values.Common adverse drug reaction
Adverse drug reaction
An adverse drug reaction is an expression that describes harm associated with the use of given medications at a normal dosage. ADRs may occur following a single dose or prolonged administration of a drug or result from the combination of two or more drugs...
s (≥1% of patients) associated with IV vancomycin include: local pain, which may be severe and/or thrombophlebitis
Thrombophlebitis
Thrombophlebitis is phlebitis related to a thrombus . When it occurs repeatedly in different locations, it is known as "Thrombophlebitis migrans" or "migrating thrombophlebitis".-Signs and symptoms:...
.
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
Nephrotoxicity
Nephrotoxicity is a poisonous effect of some substances, both toxic chemicals and medication, on the kidneys. There are various forms of toxicity. Nephrotoxicity should not be confused with the fact that some medications have a predominantly renal excretion and need their dose adjusted for the...
is an infrequent adverse effect (0.1–1% of patients), but that this is accentuated in the presence of aminoglycoside
Aminoglycoside
An aminoglycoside is a molecule or a portion of a molecule composed of amino-modifiedsugars.Several aminoglycosides function as antibiotics that are effective against certain types of bacteria...
s.
Rare adverse effects (<0.1% of patients) include: anaphylaxis
Anaphylaxis
Anaphylaxis is defined as "a serious allergic reaction that is rapid in onset and may cause death". It typically results in a number of symptoms including throat swelling, an itchy rash, and low blood pressure...
, toxic epidermal necrolysis
Toxic epidermal necrolysis
Toxic epidermal necrolysis is a rare, life-threatening dermatological condition that is usually induced by a reaction to medications...
, erythema multiforme
Erythema multiforme
Erythema multiforme is a skin condition of unknown cause, possibly mediated by deposition of immune complex in the superficial microvasculature of the skin and oral mucous membrane that usually follows an infection or drug exposure...
, red man syndrome (see below), superinfection
Superinfection
In virology, superinfection is the process by which a cell, that has previously been infected by one virus, gets coinfected with a different strain of the virus, or another virus at a later point in time. Viral superinfections of serious conditions can lead to resistant strains of the virus, which...
, thrombocytopenia
Thrombocytopenia
Thrombocytopenia is a relative decrease of platelets in blood.A normal human platelet count ranges from 150,000 to 450,000 platelets per microliter of blood. These limits are determined by the 2.5th lower and upper percentile, so values outside this range do not necessarily indicate disease...
, neutropenia
Neutropenia
Neutropenia, from Latin prefix neutro- and Greek suffix -πενία , is a granulocyte disorder characterized by an abnormally low number of neutrophils, the most important type of white blood cell...
, leucopenia
Leukopenia
Leukopenia is a decrease in the number of white blood cells found in the blood, which places individuals at increased risk of infection....
, tinnitus
Tinnitus
Tinnitus |ringing]]") is the perception of sound within the human ear in the absence of corresponding external sound.Tinnitus is not a disease, but a symptom that can result from a wide range of underlying causes: abnormally loud sounds in the ear canal for even the briefest period , ear...
, dizziness and/or ototoxicity (see below).
It has recently been emphasized that vancomycin can induce platelet-reactive antibodies in the patient, leading to severe thrombocytopenia
Thrombocytopenia
Thrombocytopenia is a relative decrease of platelets in blood.A normal human platelet count ranges from 150,000 to 450,000 platelets per microliter of blood. These limits are determined by the 2.5th lower and upper percentile, so values outside this range do not necessarily indicate disease...
and bleeding with florid petechial hemorrhages
Petechia
A petechia is a small red or purple spot on the body, caused by a minor hemorrhage ."Petechiae" refers to one of the three major classes of purpuric skin conditions. Purpuric eruptions are classified by size into three broad categories...
, ecchymoses, and wet purpura.
Intravenous vs oral administration
Vancomycin must be given intravenously (IV) for systemic therapy, since it does not cross through the intestinal lining. It is a large hydrophilic molecule that partitions poorly across the gastrointestinal mucosa. The only indication for oral vancomycin therapy is in the treatment of pseudomembranous colitisPseudomembranous colitis
Pseudomembranous colitis, a cause of antibiotic-associated diarrhea , is an infection of the colon. It is often, but not always, caused by the bacterium Clostridium difficile. Because of this, the informal name C. difficile colitis is also commonly used. The illness is characterized by...
, where it must be given orally to reach the site of infection in the colon. Following oral administration, the fecal concentration of vancomycin is around 500 µg/mL (sensitive strains of C. difficile have a mean inhibitory concentration of ≤2 µg/mL)
Inhaled vancomycin has also been used (off-label), via nebulizer
Nebulizer
In medicine, a nebulizer is a device used to administer medication in the form of a mist inhaled into the lungs....
, for treatment of various infections of the upper and lower respiratory tract.
The caustic nature of vancomycin makes IV therapy using peripheral lines a risk for thrombophlebitis. Ideally, central lines, PICCs, or infusion ports should be used.
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). This is due to the high incidence of painPain
Pain is an unpleasant sensation often caused by intense or damaging stimuli such as stubbing a toe, burning a finger, putting iodine on a cut, and bumping the "funny bone."...
and thrombophlebitis
Thrombophlebitis
Thrombophlebitis is phlebitis related to a thrombus . When it occurs repeatedly in different locations, it is known as "Thrombophlebitis migrans" or "migrating thrombophlebitis".-Signs and symptoms:...
and to avoid an infusion reaction known as the red man syndrome or red neck syndrome. This syndrome, usually appearing within 4–10 minutes after the commencement or soon after the completion of an infusion, is characterized by flushing and/or an erythematous rash that affects the face, neck, and upper torso. These findings are due to non-specific mast cell
Mast cell
A mast cell is a resident cell of several types of tissues and contains many granules rich in histamine and heparin...
degranulation and are not an IgE
IGE
IGE was one of the largest services company buying and selling virtual currencies and accounts for MMORPG. During its peak time, it had offices in Los Angeles, China , and headquarters & customer service centre in Hong Kong. IGE was one of the main monopoly in virtual economy services, also known...
-mediated allergic reaction. Less frequently, hypotension
Hypotension
In physiology and medicine, hypotension is abnormally low blood pressure, especially in the arteries of the systemic circulation. It is best understood as a physiologic state, rather than a disease. It is often associated with shock, though not necessarily indicative of it. Hypotension is the...
and angioedema
Angioedema
Angioedema or Quincke's edema is the rapid swelling of the dermis, subcutaneous tissue, mucosa and submucosal tissues. It is very similar to urticaria, but urticaria, commonly known as hives, occurs in the upper dermis...
may also occur. Symptoms may be treated or prevented with antihistamine
Antihistamine
An H1 antagonist is a histamine antagonist of the H1 receptor that serves to reduce or eliminate effects mediated by histamine, an endogenous chemical mediator released during allergic reactions...
s, including diphenhydramine
Diphenhydramine
Diphenhydramine hydrochloride is a first-generation antihistamine possessing anticholinergic, antitussive, antiemetic, and sedative properties which is mainly used to treat allergies. Like most other first-generation antihistamines, the drug also has a powerful hypnotic effect, and for this reason...
, and are less likely to occur with slow infusion.
Therapeutic drug monitoring
Vancomycin activity is considered to be time-dependent; that is, antimicrobial activity depends on the duration that the serum drug concentration exceeds the minimum inhibitory concentrationMinimum inhibitory concentration
In microbiology, minimum inhibitory concentration is the lowest concentration of an antimicrobial that will inhibit the visible growth of a microorganism after overnight incubation. Minimum inhibitory concentrations are important in diagnostic laboratories to confirm resistance of microorganisms...
(MIC) of the target organism. Thus, peak serum levels have not been shown to correlate with efficacy or toxicity – indeed concentration monitoring is unnecessary in most cases. Circumstances in which therapeutic drug monitoring
Therapeutic drug monitoring
- Background :Therapeutic drug monitoring is a branch of clinical chemistry and clinical pharmacology that specializes in the measurement of medication concentrations in blood. Its main focus is on drugs with a narrow therapeutic range, i.e. drugs that can easily be under- or overdosed...
(TDM) is warranted include: patients receiving concomitant aminoglycoside therapy, patients with (potentially) altered pharmacokinetic
Pharmacokinetics
Pharmacokinetics, sometimes abbreviated as PK, is a branch of pharmacology dedicated to the determination of the fate of substances administered externally to a living organism...
parameters, patients on haemodialysis
Hemodialysis
In medicine, hemodialysis is a method for removing waste products such as creatinine and urea, as well as free water from the blood when the kidneys are in renal failure. Hemodialysis is one of three renal replacement therapies .Hemodialysis can be an outpatient or inpatient therapy...
, patients administered high-dose or prolonged treatment, and patients with impaired renal function. In such cases, trough concentrations are measured.
Target ranges for serum vancomycin concentrations have changed over the years. Early authors suggested peak levels of 30–40 mg/L and trough levels
Trough levels
In medicine, a trough level is the lowest level that a medicine is present in the body. In a medicine that is administered periodically, the trough level should be measured just before the administration of the next dose in order to avoid overdosing...
of 5–10 mg/L,
but current recommendations are that peak levels need not be measured and that trough levels
Trough levels
In medicine, a trough level is the lowest level that a medicine is present in the body. In a medicine that is administered periodically, the trough level should be measured just before the administration of the next dose in order to avoid overdosing...
of 10-15 or 15–20 mg/L, depending on the nature of the infection and the specific needs of the patient, may be appropriate.
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 that 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 1970s, 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.Nephrotoxicity
Subsequent reviews of accumulated case reports of vancomycin-related nephrotoxicityNephrotoxicity
Nephrotoxicity is a poisonous effect of some substances, both toxic chemicals and medication, on the kidneys. There are various forms of toxicity. Nephrotoxicity should not be confused with the fact that some medications have a predominantly renal excretion and need their dose adjusted for the...
found that many of the patients had also received other known nephrotoxins, in particular, aminoglycosides. 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. 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
Cefamandole
Cefamandole is a second-generation broad-spectrum cephalosporin antibiotic. The clinically used form of cefamandole is the formate ester cefamandole nafate, a prodrug which is administered parenterally....
and benzylpenicillin
Benzylpenicillin
Benzylpenicillin, commonly known as penicillin G, is the gold standard type of penicillin. 'G' in the name 'Penicillin G' refers to 'Gold Standard'. Penicillin G is typically given by a parenteral route of administration because it is unstable in the hydrochloric acid of the stomach...
, two reputedly non-nephrotoxic antibiotics.
In addition, 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. In essence, 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 ototoxicityOtotoxicity
Ototoxicity is damage to the ear , specifically the cochlea or auditory nerve and sometimes the vestibular system, by a toxin. It is commonly medication-induced; ototoxic drugs include antibiotics such as the aminoglycoside gentamicin, loop diuretics such as furosemide, and platinum-based...
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
Therapeutic drug monitoring
- Background :Therapeutic drug monitoring is a branch of clinical chemistry and clinical pharmacology that specializes in the measurement of medication concentrations in blood. Its main focus is on drugs with a narrow therapeutic range, i.e. drugs that can easily be under- or overdosed...
of vancomycin for the purpose of maintaining "therapeutic" levels will prevent ototoxicity.
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.Intrinsic resistance
There are a few gram-positiveGram-positive
Gram-positive bacteria are those that are stained dark blue or violet by Gram staining. This is in contrast to Gram-negative bacteria, which cannot retain the crystal violet stain, instead taking up the counterstain and appearing red or pink...
bacteria that are intrinsically resistant to vancomycin: Leuconostoc
Leuconostoc
Leuconostoc is a genus of Gram-positive bacteria, placed within the family of Leuconostocaceae. They are generally ovoid cocci often forming chains. Leuconostoc spp. are intrinsically resistant to vancomycin and are catalase-negative . All species within this genus are heterofermentative and are...
and Pediococcus
Pediococcus
Pediococcus is a genus of Gram-positive lactic acid bacteria, placed within the family of Lactobacillaceae. They usually occur in pairs or tetrads, and divide along two planes of symmetry, as do the other lactic acid cocci genera Aerococcus and Tetragenococcus. They are purely homofermentative...
species, but these organisms are rare causes of disease in humans. Most Lactobacillus
Lactobacillus
Lactobacillus is a genus of Gram-positive facultative anaerobic or microaerophilic rod-shaped bacteria. They are a major part of the lactic acid bacteria group, named as such because most of its members convert lactose and other sugars to lactic acid. They are common and usually benign...
species are also intrinsically resistant to vancomycin (the exception is the finding of a few strains (but not all) of L. acidophilus
Lactobacillus acidophilus
Lactobacillus acidophilus is a species in the genus Lactobacillus. L. acidophilus is a homofermentative species, fermenting sugars into lactic acid, which grows readily at rather low pH values and has an optimum growth temperature of 37 °C . L...
).
Most gram-negative
Gram-negative
Gram-negative bacteria are bacteria that do not retain crystal violet dye in the Gram staining protocol. In a Gram stain test, a counterstain is added after the crystal violet, coloring all Gram-negative bacteria with a red or pink color...
bacteria are intrinsically resistant to vancomycin because their outer membrane is impermeable to large glycopeptide molecules (with the exception of some non-gonococcal Neisseria
Neisseria
The Neisseria is a large genus of commensal bacteria that colonize the mucosal surfaces of many animals. Of the 11 species that colonize humans, only two are pathogens. N. meningitidis and N. gonorrhoeae often cause asymptomatic infections, a commensal-like behavior...
species).
Acquired resistance
Acquired microbial resistanceAntibiotic resistance
Antibiotic resistance is a type of drug resistance where a microorganism is able to survive exposure to an antibiotic. While a spontaneous or induced genetic mutation in bacteria may confer resistance to antimicrobial drugs, genes that confer resistance can be transferred between bacteria in a...
to vancomycin is a growing problem, in particular, within healthcare facilities such as hospitals. While newer alternatives to vancomycin exist, such as Linezolid
Linezolid
Linezolid is a synthetic antibiotic used for the treatment of serious infections caused by Gram-positive bacteria that are resistant to several other antibiotics...
(2000) and daptomycin
Daptomycin
Daptomycin is a novel lipopeptide antibiotic used in the treatment of certain infections caused by Gram-positive organisms. It is a naturally occurring compound found in the soil saprotroph Streptomyces roseosporus. Its distinct mechanism of action means that it may be useful in treating infections...
(2003), the widespread use of vancomycin makes resistance to the drug a significant worry, especially for individual patients if resistant infections are not quickly identified and the patient continues the ineffective treatment. Vancomycin-resistant Enterococcus
Vancomycin-Resistant Enterococcus
Vancomycin-resistant Enterococcus, or vancomycin-resistant enterococci , are bacterial strains of the genus Enterococcus that are resistant to the antibiotic vancomycin. To become VRE, vancomycin-sensitive enterococci typically obtain new DNA in the form of plasmids or transposons which encode...
(VRE) emerged in 1987. Vancomycin resistance emerged in more common pathogenic organisms during the 1990s and 2000s, including vancomycin-intermediate Staphylococcus aureus
Vancomycin-resistant Staphylococcus aureus
Vancomycin-resistant Staphylococcus aureus refers to strains of Staphylococcus aureus that have become resistant to the glycopeptide antibiotic vancomycin. With the increase of staphylococcal resistance to methicillin, vancomycin is often a treatment of choice in infections with...
(VISA) and vancomycin-resistant Staphylococcus aureus
Vancomycin-resistant Staphylococcus aureus
Vancomycin-resistant Staphylococcus aureus refers to strains of Staphylococcus aureus that have become resistant to the glycopeptide antibiotic vancomycin. With the increase of staphylococcal resistance to methicillin, vancomycin is often a treatment of choice in infections with...
(VRSA). 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 involves the alteration to the terminal amino acid residues of the NAM/NAG-peptide subunits, under normal conditions, D-alanyl-D-alanine, to which vancomycin binds. The D-alanyl-D-lactate variation results in the loss of one hydrogen-bonding interaction (4, as opposed to 5 for D-alanyl-D-alanine) possible between vancomycin and the peptide. This loss of just one point of interaction results in a 1000-fold decrease in affinity. The D-alanyl-D-serine variation causes a six-fold loss of affinity between vancomycin and the peptide, likely due to steric hindrance.
In enterococci, this modification appears to be due to the expression of an enzyme that 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 teicoplaninTeicoplaninTeicoplanin is an antibiotic used in the prophylaxis and treatment of serious infections caused by Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus and Enterococcus faecalis. It is a glycopeptide antibiotic extracted from Actinoplanes teichomyceticus, with a similar...
; 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
2011: A variant of vancomycin has been tested that binds to the lactate variation and also binds well to the original target, thus reinstates potent antimicrobial activity.
See also
- Drug resistanceDrug resistanceDrug resistance is the reduction in effectiveness of a drug such as an antimicrobial or an antineoplastic in curing a disease or condition. When the drug is not intended to kill or inhibit a pathogen, then the term is equivalent to dosage failure or drug tolerance. More commonly, the term is used...
- Antibiotic resistanceAntibiotic resistanceAntibiotic resistance is a type of drug resistance where a microorganism is able to survive exposure to an antibiotic. While a spontaneous or induced genetic mutation in bacteria may confer resistance to antimicrobial drugs, genes that confer resistance can be transferred between bacteria in a...
- Methicillin-resistant Staphylococcus aureusMethicillin-resistant Staphylococcus aureusMethicillin-resistant Staphylococcus aureus is a bacterium responsible for several difficult-to-treat infections in humans. It is also called multidrug-resistant Staphylococcus aureus and oxacillin-resistant Staphylococcus aureus...
- Vancomycin-resistant Staphylococcus aureusVancomycin-resistant Staphylococcus aureusVancomycin-resistant Staphylococcus aureus refers to strains of Staphylococcus aureus that have become resistant to the glycopeptide antibiotic vancomycin. With the increase of staphylococcal resistance to methicillin, vancomycin is often a treatment of choice in infections with...
- Vancomycin-resistant enterococcusVancomycin-Resistant EnterococcusVancomycin-resistant Enterococcus, or vancomycin-resistant enterococci , are bacterial strains of the genus Enterococcus that are resistant to the antibiotic vancomycin. To become VRE, vancomycin-sensitive enterococci typically obtain new DNA in the form of plasmids or transposons which encode...