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51-418: Vancomycin is a glycopeptide antibiotic medication used to treat certain bacterial infections . It is administered intravenously ( injection into a vein ) to treat complicated skin infections , bloodstream infections , endocarditis , bone and joint infections, and meningitis caused by methicillin-resistant Staphylococcus aureus . Blood levels may be measured to determine the correct dose. Vancomycin

102-467: A "first-in-class" antibiotic, representing glycolipodepsipeptide antibiotics . Bleomycin also has a different core. Its mode of action is also unrelated to the cell wall, instead causing DNA damage in tumor cells. Due to their toxicity, the use of first-generation glycopeptide antibiotics is restricted to patients who are critically ill, who have a demonstrated hypersensitivity to the β-lactams , or who are infected with β-lactam-resistant species, as in

153-413: Is 500 mg every 6 hours or 1000 mg every 12 hours, with modification to achieve a therapeutic range as needed. The recommended oral dosage in the treatment of antibiotic-induced pseudomembranous enterocolitis is 125 to 500 mg every 6 hours for 7 to 10 days. Dose optimization and target attainment of vancomycin in children involves adjusting the dosage to maximize effectiveness while minimizing

204-453: Is a last-resort medication for the treatment of sepsis and lower respiratory tract , skin, and bone infections caused by Gram-positive bacteria. The minimum inhibitory concentration susceptibility data for a few medically significant bacteria are: Common side effects associated with oral vancomycin administration (used to treat intestinal infections) include: Serum vancomycin levels may be monitored in an effort to reduce side effects, but

255-579: Is a type of glycopeptide antibiotic and works by blocking the construction of a cell wall . Vancomycin was approved for medical use in the United States in 1958. It is on the World Health Organization's List of Essential Medicines . The WHO classifies vancomycin as critically important for human medicine. It is available as a generic medication. Vancomycin is made by the soil bacterium Amycolatopsis orientalis . Vancomycin

306-495: 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 of the long polymers of N -acetylmuramic acid (NAM) and N -acetylglucosamine (NAG) that form the backbone strands of the bacterial cell wall, and prevents

357-426: Is also taken orally (by mouth) to treat Clostridioides difficile infections . When taken orally, it is poorly absorbed. Common side effects include pain in the area of injection and allergic reactions . Occasionally, hearing loss , low blood pressure , or bone marrow suppression occur. Safety in pregnancy is not clear, but no evidence of harm has been found, and it is likely safe for use when breastfeeding . It

408-404: Is also used for dose optimization of vancomycin in treating children. Target ranges for serum vancomycin concentrations have changed over the years. Early authors suggested peak levels of 30 to 40 mg/L and trough levels of 5 to 10 mg/L, but current recommendations are that peak levels need not be measured and that trough levels of 10 to 15 mg/L or 15 to 20 mg/L, depending on

459-406: Is assembled through NRPS, the non-proteinogenic amino acids are first synthesized. L -tyrosine is modified to become the β-hydroxytyrosine (β-HT) and 4-hydroxyphenylglycine (4-Hpg) residues. 3,5 dihydroxyphenylglycine ring (3,5-DPG) is derived from acetate. Nonribosomal peptide synthesis occurs through distinct modules that can load and extend the protein by one amino acid per module through

510-734: Is considered time-dependent; that is, antimicrobial activity depends on how long the serum drug concentration exceeds the minimum inhibitory concentration 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 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. Therapeutic drug monitoring

561-418: Is in the treatment of pseudomembranous colitis, where it must be given orally to reach the site of infection in the colon. After oral administration, the fecal concentration of vancomycin is around 500 μg/mL (sensitive strains of Clostridioides difficile have a mean inhibitory concentration of ≤2 μg/mL) Inhaled vancomycin can also be used off-label , via nebulizer , to treat various infections of

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612-528: Is indicated for the treatment of serious, life-threatening infections by Gram-positive bacteria of both aerobic and anaerobic types that are unresponsive to other antibiotics. The increasing emergence of vancomycin-resistant enterococci has resulted in the development of guidelines for use by the Centers for Disease Control Hospital Infection Control Practices Advisory Committee. These guidelines restrict use of vancomycin to these indications: Vancomycin

663-536: Is most prevalent at the proximal tubule, which is further supported by urinary biomarkers, such as kidney injury molecule-1 (KIM-1), clusterin, and osteopontin (OPN). In humans, insulin-like growth factor binding protein 7 (IGFBP7) as part of the nephrocheck test. The mechanisms underlying the pathogenesis of vancomycin nephrotoxicity are multifactorial but include interstitial nephritis, tubular injury due to oxidative stress, and cast formation. Therapeutic drug monitoring can be used during vancomycin therapy to minimize

714-478: Is much better at penetrating leukocytes and phagocytes than vancomycin. Since 2002, isolates of vancomycin-resistant Staphylococcus aureus (VRSA) have been found in the USA and other countries. Glycopeptides have typically been considered the last effective line of defense for cases of MRSA, however, several newer classes of antibiotics have proven to have activity against MRSA- including, in 2000, linezolid of

765-412: Is of aerobic or anaerobic type. Specifically, vancomycin forms hydrogen bonds with the D -alanyl- D -alanine ( D -Ala- D -Ala) peptide motif of the peptidoglycan precursor, a crucial component of the bacterial cell wall. Peptidoglycan is a polymer that provides structural support to the bacterial cell wall. The peptidoglycan precursor is synthesized in the cytoplasm and then transported across

816-416: Is reversible once therapy has stopped. Over 90% of the dose is excreted in the urine, therefore there is a risk of accumulation in patients with renal impairment, so therapeutic drug monitoring (TDM) is recommended. Oral preparations of vancomycin are available, however, they are not absorbed from the lumen of the gut, so are of no use in treating systemic infections. The oral preparations are formulated for

867-404: Is that clearly related cases of vancomycin ototoxicity are rare. The association between vancomycin serum levels and ototoxicity is also uncertain. Cases of ototoxicity have been reported in patients whose vancomycin serum level exceeded 80 μg/mL, but cases have also been reported in patients with therapeutic levels. Thus it remains unknown whether therapeutic drug monitoring of vancomycin for

918-522: 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

969-485: Is usually given intravenously, as an infusion, and can cause tissue necrosis and phlebitis at the injection site if given too rapidly. Pain at the site of injection is indeed a common adverse event. One of the side effects is red man syndrome , an idiosyncratic reaction to bolus caused by histamine release. Some other side-effects of vancomycin are nephrotoxicity including kidney failure and interstitial nephritis, blood disorders including neutropenia, and deafness, which

1020-439: The D -Ala- D -Ala peptide motif of the peptidoglycan precursor, thereby preventing its processing by the transglycosylase; as such, vancomycin disrupts the transglycosylation activity of the cell wall synthesis process. The disruption leads to an incomplete and corrupted cell wall, which makes the replicating bacteria vulnerable to external forces such as osmotic pressure, so that the bacteria cannot survive and are eliminated by

1071-563: The United States , vancomycin is approved by the Food and Drug Administration for intravenous and oral administration. Vancomycin must be given intravenously for systemic therapy since it is poorly absorbed from the intestine. It is a large hydrophilic molecule that partitions poorly across the gastrointestinal mucosa . Due to its short half-life, it is often injected twice daily. The only approved indication for oral vancomycin therapy

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1122-399: 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) 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

1173-427: The oxazolidinone class, and in 2003 daptomycin of the lipopeptide class. Several derivatives of vancomycin are currently being developed, including oritavancin and dalbavancin (both lipoglycopeptides ). Possessing longer half-lives than vancomycin, these newer candidates may demonstrate improvements over vancomycin due to less frequent dosing and activity against vancomycin-resistant bacteria. Vancomycin

1224-431: The 1980s until 2008 recommended vancomycin trough concentrations between 5 and 15 μg/mL. Concern for treatment failures prompted recommendations for higher dosing (troughs 15 to 20 μg/mL) for serious infection, and acute kidney injury (AKI) rates attributable to the vancomycin increased. Importantly, the risk of AKI increases with co-administration of other known nephrotoxins, in particular aminoglycosides. Furthermore,

1275-523: The NRPSs only contain 3 epimerization domains. The origin of D-Leu at residue 1 is unknown. The three peptide syntheses are at the start of the region of the bacterial genome linked with antibiotic biosynthesis, and span 27 kb. β-hydroxytyrosine (β-HT) is synthesized before incorporation into the heptapeptide backbone. L-tyrosine is activated and loaded on the NRPS VpsD, hydroxylated by OxyD, and released by

1326-429: The U.S. It has more fatty acid chains than vancomycin and is considered to be 50 to 100 times more lipophilic. Teicoplanin also has an increased half-life compared to vancomycin, as well as having better tissue penetration. It can be two to four times more active than vancomycin, but it does depend upon the organism. Teicoplanin is more acidic, forming water-soluble salts, so it can be given intramuscularly. Teicoplanin

1377-671: The X domain in the 7th NRPS module, which is unique to glycopeptide antibiotic biosynthesis. The cross-linked heptapeptide is then released by the action of the TE domain, and methyltransferase Vmt then N -methylates the terminal leucine residue. GtfE then joins D-glucose to the phenolic oxygen of residue 4, followed by the addition of vancosamine catalyzed by GtfD. Some of the glycosyltransferases capable of glycosylating vancomycin and related nonribosomal peptides display notable permissivity and have been used to generate libraries of differentially glycosylated analogs through glycorandomization . Both

1428-428: The addition of new units to the peptidoglycan. Of this core class, one may distinguish multiple generations: the first generation includes vancomycin and teicoplanin, while the semisynthetic second generation includes lipoglycopeptides like telavancin, oritavancin and dalbavancin. The extra lipophilicity not only enhances Lipid II binding but also creates a second mechanism of action whereby the antibiotic dissolves into

1479-467: 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 NRPS enzymes (peptide synthase VpsA, VpsB, and VpsC) are responsible for assembling the heptapeptide. (Figure 2). VpsA codes for modules 1, 2, and 3. VpsB codes for modules 4, 5, and 6, and VpsC codes for module 7. The vancomycin aglycone contains 4 D-amino acids, although

1530-498: The backbone polymers from cross-linking with each other. Vancomycin is one of the few antibiotics used in plant tissue culture to eliminate Gram-positive bacterial infection. It has relatively low toxicity to plants. Glycopeptide antibiotic Some members of this class of drugs inhibit the synthesis of cell walls in susceptible microbes by inhibiting peptidoglycan synthesis. The core class (including vancomycin) binds to acyl- D -alanyl- D -alanine in lipid II , preventing

1581-471: The case of methicillin-resistant Staphylococcus aureus . These antibiotics are effective principally against Gram-positive cocci. First-generation examples exhibit a narrow spectrum of action and are bactericidal only against the enterococci . Some tissues are not penetrated very well by glycopeptides, and they do not penetrate into the cerebrospinal fluid . The second-generation glycopeptides, or "lipoglycopeptides", have better binding to Lipid II due to

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1632-596: The commencement or soon after the completion of an infusion and is characterized by flushing and/or an erythematous rash that affects the face, neck, and upper torso, attributed to the release of histamine from mast cells. This reaction is caused by the interaction of vancomycin with MRGPRX2 , a GPCR-mediating IgE-independent mast cell degranulation. Less frequently, hypotension and angioedema occur. Symptoms may be treated or prevented with antihistamines , including diphenhydramine , and are less likely to occur with slow infusion. The recommended intravenous dosage in adults

1683-466: The cytoplasmic membrane to the periplasmic space, where it is assembled into the cell wall. The assembly process involves two enzymatic activities: transglycosylation and transpeptidation. Transglycosylation involves the polymerization of the peptidoglycan precursor into long chains, while transpeptidation involves the cross-linking of these chains to form a three-dimensional mesh-like structure. Vancomycin inhibits bacterial cell wall synthesis by binding to

1734-438: The immune system. Gram-negative bacteria are insensitive to vancomycin due to their different cell wall morphology. The outer membrane of Gram-negative bacteria contains lipopolysaccharide, which acts as a barrier to vancomycin penetration. That is why vancomycin is mainly used to treat infections caused by Gram-positive bacteria (except some nongonococcal species of Neisseria ). The large hydrophilic molecule of vancomycin

1785-734: The kidneys ( nephrotoxicity ) and to the hearing ( ototoxicity ) were side effects of the early, impure versions of vancomycin, and were prominent in clinical trials conducted in the mid-1950s. Later trials using purer forms of vancomycin found nephrotoxicity is an infrequent adverse effect (0.1% to 1% of patients), but this is accentuated in the presence of aminoglycosides . Rare adverse effects associated with intravenous vancomycin (<0.1% of patients) include anaphylaxis , toxic epidermal necrolysis , erythema multiforme , superinfection , thrombocytopenia , neutropenia , leukopenia , tinnitus , dizziness and/or ototoxicity , and DRESS syndrome . Vancomycin can induce platelet-reactive antibodies in

1836-430: The linear heptapeptide to cross-linked, glycosylated vancomycin, six enzymes are required. The enzymes OxyA, OxyB, OxyC, and OxyD are cytochrome P450 enzymes. OxyB catalyzes oxidative cross-linking between residues 4 and 6, OxyA between residues 2 and 4, and OxyC between residues 5 and 7. This cross-linking occurs while the heptapeptide is covalently bound to the PCP domain of the 7th NRPS module. These P450s are recruited by

1887-581: The lipophilic moieties, expanding the antibacterial spectrum. Telavancin also has a hydrophilic moiety attached to enhance tissue distribution and reduce nephrotoxicity. Vancomycin was isolated in 1953 and used clinically by 1958, while teicoplanin was discovered in 1978 and became clinically-available in 1984. Telavancin is a semi-synthetic lipoglycopeptide derivative of vancomycin approved by FDA in 2009. Teicoplanin has historically been more widely marketed - and thus more used - in Europe compared to

1938-565: The membrane and makes it more permeable. Corbomycin and complestatin are structurally and ancestrally related to vancomycin, but they work by inhibiting autolysins through binding to peptidoglycan, therefore preventing cell division, neither is an approved drug. Ramoplanin, although a "glycopeptide" in the literal sense, has a quite different structural core. It not only binds to Lipid II but also attacks MurG and transglycosylases (glycosyltransferases) which polymerize amino acid/sugar building blocks into peptidoglycan. It has been described as

1989-548: The nature of the infection and the specific patient's needs, may be appropriate. Measuring vancomycin concentrations to calculate doses optimizes therapy in patients with augmented renal clearance . Vancomycin is a branched tricyclic glycosylated nonribosomal peptide produced by the Actinomycetota species Amycolatopsis orientalis (formerly designated Nocardia orientalis ). Vancomycin exhibits atropisomerism —it has multiple chemically distinct rotamers owing to

2040-596: The nephrotoxic effect probably increases when vancomycin is added to nephrotoxins such as aminoglycosides. A dose- or serum level-effect relationship has not been established. Vancomycin is recommended to be administered in a dilute solution slowly, over at least 60 min (maximum rate of 10 mg/min for doses >500 mg) due to the high incidence of pain and thrombophlebitis and to avoid an infusion reaction known as vancomycin flushing reaction. This phenomenon has been often clinically referred to as "red man syndrome". The reaction usually appears within 4 to 10 min after

2091-475: The patient, leading to severe thrombocytopenia and bleeding with florid petechial hemorrhages , ecchymoses , and wet purpura . Historically, vancomycin has been considered a nephrotoxic and ototoxic drug, based on numerous case reports in the medical literature following initial approval by the FDA in 1958. But as its use increased with the spread of MRSA beginning in the 1970s, toxicity risks were reassessed. With

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2142-431: The purpose of maintaining "therapeutic" levels prevents ototoxicity. Still, therapeutic drug monitoring can be used during vancomycin therapy to minimize the risk of ototoxicity associated with excessive drug exposure. Another area of controversy and uncertainty is whether and to what extent vancomycin increases the toxicity of other nephrotoxins. Clinical studies have yielded various results, but animal models indicate that

2193-465: The removal of impurities present in earlier formulations of the drug, and with the introduction of therapeutic drug monitoring , the risk of severe toxicity has been reduced. The extent of nephrotoxicity for vancomycin remains controversial. In 1980s, vancomycin with a purity > 90% was available, and kidney toxicity defined by an increase in serum creatinine of at least 0.5 mg/dL occurred in only about 5% of patients. But dosing guidelines from

2244-524: The risk of adverse effects, specifically acute kidney injury. Dose optimization is achieved by therapeutic drug monitoring (TDM), which allows measurement of vancomycin levels in the blood. TDM using area under the curve (AUC)-guided dosing, preferably with Bayesian forecasting, is recommended to ensure that the AUC0-24h/minimal inhibitory concentration (MIC) ratio is maintained above a certain threshold (400-600) associated with optimal efficacy. In

2295-444: The risk of nephrotoxicity associated with excessive drug exposure. Immunoassays are commonly utilized for measuring vancomycin levels. In children, concomitant administration of vancomycin and piperacillin/tazobactam has been associated with an elevated incidence of AKI relative to other antibiotic regimens. Attempts to establish rates of vancomycin-induced ototoxicity are even more difficult due to lack of good data. The consensus

2346-425: The rotational restriction of some of the bonds. The form present in the drug is the thermodynamically more stable conformer . Vancomycin is made by the soil bacterium Amycolatopsis orientalis . Vancomycin biosynthesis occurs primarily via three nonribosomal protein syntheses (NRPSs) VpsA, VpsB, and VpsC. The enzymes determine the amino acid sequence during its assembly through its 7 modules. Before vancomycin

2397-450: The sort of infections treated with vancomycin may also cause AKI, and sepsis is the most common cause of AKI in critically ill patients. Finally, studies in humans are mainly associations studies, where the cause of AKI is usually multifacotorial. Animal studies have demonstrated that higher doses and longer duration of vancomycin exposure correlates with increased histopathologic damage and elevations in urinary biomarkers of AKI.37-38 Damage

2448-457: The thioesterase Vhp. The timing of the chlorination by halogenase VhaA during biosynthesis is undetermined, but is proposed to occur before the complete assembly of the heptapeptide. After the linear heptapeptide molecule is synthesized, vancomycin must undergo further modifications, such as oxidative cross-linking and glycosylation , in trans by distinct enzymes, referred to as tailoring enzymes, to become biologically active (Figure 3). To convert

2499-460: The upper and lower respiratory tract. Rectal administration is an off-label use of vancomycin for the treatment of Clostridioides difficile infection. Plasma level monitoring of vancomycin is necessary due to the drug's biexponential distribution, intermediate hydrophilicity, and potential for ototoxicity and nephrotoxicity, especially in populations with poor renal function and/or increased propensity to bacterial infection. Vancomycin activity

2550-413: The value of such monitoring has been questioned. Peak and trough levels are usually monitored, and for research purposes the area under the concentration curve is also sometimes used. Toxicity is best monitored by looking at trough values. Immunoassays are commonly used to measure vancomycin levels. Common adverse drug reactions (≥1% of patients) associated with intravenous vancomycin include: Damage to

2601-558: The vancomycin aglycone and the complete vancomycin molecule have been targets successfully reached by total synthesis . The target was first achieved by David Evans in October 1998, KC Nicolaou in December 1998, Dale Boger in 1999, and more selectively synthesized again by Boger in 2020. Vancomycin targets bacterial cell wall synthesis by binding to the basic building block of the bacterial cell wall of Gram-positive bacteria, whether it

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