Vancomycin

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Vancomycin
Vancomycin.svg
Vancomycin-from-xtal-1996-3D-balls.png
Clinical data
Pronunciation /væŋkəˈmaɪsɪn/ [1] [2]
Trade names Vancocin, others [3]
AHFS/Drugs.com Monograph
MedlinePlus a604038
License data
Pregnancy
category
Routes of
administration 		Intravenous, oral
Drug class Glycopeptide antibiotic
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability Negligible (oral)
Metabolism Excreted unchanged
Elimination half-life 4 h to 11 h (adults, normal renal function)
6 d to 10 d (adults, impaired renal function)
Excretion urine (IV), feces (oral)
Identifiers
  • (1S,2R,18R,19R,22S,25R,28R,40S)- 48- {[(2S,3R,4S,5S,6R)- 3- {[(2S,4S,5S,6S)- 4- amino- 5- hydroxy- 4,6- dimethyloxan- 2- yl]oxy}- 4,5- dihydroxy- 6- (hydroxymethyl)oxan- 2- yl]oxy}- 22- (carbamoylmethyl)- 5,15- dichloro- 2,18,32,35,37- pentahydroxy- 19- [(2R)- 4- methyl- 2- (methylamino)pentanamido]- 20,23,26,42,44- pentaoxo- 7,13- dioxa- 21,24,27,41,43- pentaazaoctacyclo[26.14.2.23,6.214,17.18,12.129,33.010,25.034,39]pentaconta- 3,5,8(48),9,11,14,16,29(45),30,32,34,36,38,46,49- pentadecaene- 40- carboxylic acid
CAS Number
PubChem CID
PubChemSID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.014.338 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C66H75Cl2N9O24
Molar mass 1449.27 g·mol−1
3D model (JSmol)
  • C[C@H]1[C@H]([C@@](C[C@@H](O1)O[C@@H]2[C@H]([C@@H]([C@H](O[C@H]2Oc3c4cc5cc3Oc6ccc(cc6Cl)[C@H]([C@H](C(=O)N[C@H](C(=O)N[C@H]5C(=O)N[C@@H]7c8ccc(c(c8)-c9c(cc(cc9O)O)[C@H](NC(=O)[C@H]([C@@H](c1ccc(c(c1)Cl)O4)O)NC7=O)C(=O)O)O)CC(=O)N)NC(=O)[C@@H](CC(C)C)NC)O)CO)O)O)(C)N)O
  • InChI=1S/C66H75Cl2N9O24/c1-23(2)12-34(71-5)58(88)76-49-51(83)26-7-10-38(32(67)14-26)97-40-16-28-17-41(55(40)101-65-56(54(86)53(85)42(22-78)99-65)100-44-21-66(4,70)57(87)24(3)96-44)98-39-11-8-27(15-33(39)68)52(84)50-63(93)75-48(64(94)95)31-18-29(79)19-37(81)45(31)30-13-25(6-9-36(30)80)46(60(90)77-50)74-61(91)47(28)73-59(89)35(20-43(69)82)72-62(49)92/h6-11,13-19,23-24,34-35,42,44,46-54,56-57,65,71,78-81,83-87H,12,20-22,70H2,1-5H3,(H2,69,82)(H,72,92)(H,73,89)(H,74,91)(H,75,93)(H,76,88)(H,77,90)(H,94,95)/t24-,34+,35-,42+,44-,46+,47+,48-,49+,50-,51+,52+,53+,54-,56+,57+,65-,66-/m0/s1 Yes check.svgY
  • Key:MYPYJXKWCTUITO-LYRMYLQWSA-N Yes check.svgY
   (verify)

Vancomycin is a glycopeptide antibiotic medication used to treat a number of bacterial infections. [7] It is used intravenously (injection into a vein) as a treatment for complicated skin infections, bloodstream infections, endocarditis, bone and joint infections, and meningitis caused by methicillin-resistant Staphylococcus aureus. [8] Blood levels may be measured to determine the correct dose. [9] Vancomycin is also taken orally (by mouth) as a treatment for severe Clostridium difficile colitis. [7] When taken orally it is poorly absorbed. [7]

Contents

Common side effects include pain in the area of injection and allergic reactions. [7] Occasionally, hearing loss, low blood pressure, or bone marrow suppression occur. [7] Safety in pregnancy is not clear, but no evidence of harm has been found, [7] [10] and it is likely safe for use when breastfeeding. [11] It is a type of glycopeptide antibiotic and works by blocking the construction of a cell wall. [7]

Vancomycin was approved for medical use in the United States in 1958. [12] It is on the World Health Organization's List of Essential Medicines. [13] [14] The World Health Organization classifies vancomycin as critically important for human medicine. [15] It is available as a generic medication. [9] Vancomycin is made by the soil bacterium Amycolatopsis orientalis . [7]

Medical uses

Vancomycin is indicated for the treatment of serious, life-threatening infections by Gram-positive (aerobic and/or anaerobic) [16] bacteria unresponsive to other antibiotics. [17] [18] [19]

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: [20] [21]

Spectrum of susceptibility

Vancomycin is considered 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: [24]

Side effects

Oral administration

Common side effects associated with oral vancomycin administration (used to treat intestinal infections) [25] include:

Intravenous administration

Serum vancomycin levels may be monitored in an effort to reduce side effects. [26] Still, the value of such monitoring has been questioned. [27] Peak and trough levels are usually monitored, and for research purposes, the area under the concentration curve is also sometimes used. [28] Toxicity is best monitored by looking at trough values. [28] Immunoassays are commonly used to measure levels of vancomycin. [26]

Common adverse drug reactions (≥1% of patients) associated with intravenous (IV) vancomycin include:

Damage to the kidneys (nephrotoxicity) and to the hearing (ototoxicity) were side effects of the early impure versions of vancomycin, and these were prominent in the clinical trials conducted in the mid-1950s. [31] [32] 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. [33]

Rare adverse effects associated with intravenous (IV) vancomycin (<0.1% of patients) include: anaphylaxis, toxic epidermal necrolysis, erythema multiforme, superinfection, thrombocytopenia, neutropenia, leukopenia, tinnitus, dizziness and/or ototoxicity, and DRESS syndrome. [34]

Vancomycin can induce platelet-reactive antibodies in the patient, leading to severe thrombocytopenia and bleeding with florid petechial hemorrhages, ecchymoses, and wet purpura. [35]

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. However, as the use of vancomycin increased with the spread of MRSA beginning in the 1970s, toxicity risks were reassessed. With the removal of impurities present in earlier formulations of the drug, [31] and with the introduction of therapeutic drug monitoring, the risk for severe toxicity has been reduced.

Nephrotoxicity

The extent of nephrotoxicity for vancomycin remains controversial. [36] 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. [36] However, dosing guidelines from the 1980s until 2008 recommended vancomycin trough concentrations between 5 and 15 μg/ml. [37] 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. [38]

Importantly, the risk of AKI increases with co-administration of other known nephrotoxins, in particular, aminoglycosides. Furthmore, 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.[ citation needed ]

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 [39] Damage 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), [40] and in humans, insulin-like growth factor binding protein 7 (IGFBP7) as part of the nephrocheck test. [41]

The mechanisms that underlie the pathogenesis of vancomycin nephrotoxicity are multifactorial but include interstitial nephritis, tubular injury due to oxidative stress, and cast formation. [38]

Therapeutic drug monitoring can be used during vancomycin therapy to minimize the risk of nephrotoxicity associated with excessive drug exposure. Immunoassays are commonly utilized for measuring vancomycin levels. [26]

In children, the concomitant administration of vancomycin and piperacillin/tazobactam has been associated with an elevated incidence of AKI, relative to other antibiotic regimens. [42]

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. [43] [44] 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, [45] cases have been reported in patients with therapeutic levels, as well. Thus, whether therapeutic drug monitoring of vancomycin for the purpose of maintaining "therapeutic" levels will prevent ototoxicity also remains unproven. [45] Still, therapeutic drug monitoring can be used during vancomycin therapy to minimize the risk of ototoxicity associated with excessive drug exposure. [26]

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 some increased nephrotoxic effect probably occurs when vancomycin is added to nephrotoxins such as aminoglycosides. However, a dose- or serum level-effect relationship has not been established.[ citation needed ]

Vancomycin Flushing Reaction (aka "Red man syndrome")

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) [20] 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 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. [46] Less frequently, hypotension and angioedema may also occur. Symptoms may be treated or prevented with antihistamines, including diphenhydramine, and are less likely to occur with slow infusion. [47] [48]

Dosing considerations

The recommended intravenous dosage in adults is 500 mg iv 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. [49]

Dose optimization and target attainment of vancomycin in children involves adjusting the dosage of the antibiotic to maximize its effectiveness while minimizing the risk of adverse effects, specifically acute kidney injury. Dose optimization is achieved through therapeutic drug monitoring (TDM), which allows to measure vancomycin levels in the blood and tailor the dosage accordingly. 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. [50]

Routes of administration

In the United States, vancomycin is approved by the Food and Drug Administration for either intravenous or oral administration. [25]

Intravenous

Vancomycin must be given intravenously (IV) 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 short half-life, it is often injected twice daily. [51]

Oral

The only approved 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. Following oral administration, the fecal concentration of vancomycin is around 500 µg/mL [52] (sensitive strains of Clostridium difficile have a mean inhibitory concentration of ≤2 µg/mL [53] )

Inhaled (off-label)

Inhaled vancomycin can also be used off-label, [54] via nebulizer, for the treatment of various infections of the upper and lower respiratory tract. [55] [56] [57] [58] [59]

Rectal (off-label)

Rectal administration is an off-label use of vancomycin for the treatment of Clostridium difficile infection. [25]

Therapeutic drug monitoring

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 is considered to be time-dependent; that is, antimicrobial activity depends on the duration that 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. [20] [27] [60] [61]

Therapeutic drug monitoring is also used for dose optimization of vancomycin in treating children. [50]

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, [62] 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 the nature of the infection and the specific needs of the patient, may be appropriate. [63] [64] Using measured vancomycin concentrations to calculate doses optimizes therapy in patients with augmented renal clearance. [65]

Chemistry

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 the rotational restriction of some of the bonds. The form present in the drug is the thermodynamically more stable conformer.[ citation needed ]

Biosynthesis

Vancomycin is made by the soil bacterium Amycolatopsis orientalis . [7]

Figure 1: Modules and domains of vancomycin assembly Vancomycin Modules.png
Figure 1: Modules and domains of vancomycin assembly

Vancomycin biosynthesis occurs primarily via three nonribosomal protein syntheses (NRPSs) VpsA, VpsB, and VpsC. [66] The enzymes determine the amino acid sequence during its assembly through its 7 modules. Before vancomycin 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. [67]

Figure 2: Linear heptapeptide, which consists of modified aromatic rings Linear heptapeptide of Vancomycin.png
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 per module through the amide bond formation at the contact sites of the activating domains. [68] 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 [69] [70] 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. [71] 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.[ citation needed ]

Figure 3: Modifications necessary for vancomycin to become biologically active Biosynthesis of Vancomycin.png
Figure 3: Modifications necessary for vancomycin to become biologically active

A set of NRPS enzymes (peptide synthase VpsA, VpsB, and VpsC) are responsible for assembling the heptapeptide. (Figure 2). [68] 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 the NRPSs only contain 3 epimerization domains. The origin of D-Leu at residue 1 is not known. The three peptide syntheses are located at the start of the region of the bacterial genome linked with antibiotic biosynthesis, and span 27 kb. [68]

β-hydroxytyrosine (β-HT) is synthesized prior to incorporation into the heptapeptide backbone. L-tyrosine is activated and loaded on the NRPS VpsD, hydroxylated by OxyD, and released by the thioesterase Vhp. [72] The timing of the chlorination by halogenase VhaA during biosynthesis is currently undetermined, but is proposed to occur before the complete assembly of the heptapeptide. [73]

After the linear heptapeptide molecule is synthesized, vancomycin has to undergo further modifications, such as oxidative cross-linking and glycosylation, in trans[ clarification needed ] by distinct enzymes, referred to as tailoring enzymes, to become biologically active (Figure 3). To convert 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 the X domain present in the 7th NRPS module, which is unique to glycopeptide antibiotic biosynthesis. [74] 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.[ citation needed ]

Some of the glycosyltransferases capable of glycosylating vancomycin and related nonribosomal peptides display notable permissivity and have been employed for generating libraries of differentially glycosylated analogs through a process known as glycorandomization. [75] [76] [77]

Total synthesis

Both the vancomycin aglycone [78] [79] and the complete vancomycin molecule [80] 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 has recently been more selectively synthesized again by Dale Boger in 2020.

Mechanism of action

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 Vancomysin AntimicrobAgentsChemother 1990 1342 commons.jpg
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

Vancomycin targets bacterial cell wall synthesis by binding to the basic building block of the bacterial cell wall of Gram-positive bacteria, whether it is of aerobic or anaerobic class. [16] 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. [17]

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 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. [17]

Vancomycin inhibits bacterial cell wall synthesis by binding to 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 the immune system. [17]

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 [17] (except some nongonococcal species of Neisseria ). [82] [83]

The large hydrophilic molecule of vancomycin 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 the backbone polymers from cross-linking with each other. [84]

Vancomycin resistance.svg
Mechanism of vancomycin action and resistance: This diagram shows only one of two ways vancomycin acts against bacteria (inhibition of cell wall cross-linking) and only one of many ways that bacteria can become resistant to it.
  1. Vancomycin is added to the bacterial environment while it is trying to synthesize new cell wall. Here, the cell wall strands have been synthesized, but not yet cross-linked.
  2. Vancomycin recognizes and binds to the two D-ala residues on the end of the peptide chains. However, in resistant bacteria, the last D-ala residue has been replaced by a D-lactate, so vancomycin cannot bind.
  3. In the resistant bacteria, cross-links are successfully formed; still, in the nonresistant (sensitive) bacteria, the vancomycin bound to the peptide chains prevents them from interacting properly with the cell wall cross-linking enzyme.
  4. In the resistant bacteria, stable cross-links are formed. In the sensitive bacteria, cross-links cannot be formed and the cell wall falls apart.

Plant tissue culture

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. [85] [86]

Antibiotic resistance

Intrinsic resistance

A few Gram-positive bacteria are intrinsically resistant to vancomycin: Leuconostoc and Pediococcus species, but these organisms rarely cause diseases in humans. [87] Most Lactobacillus species are also intrinsically resistant to vancomycin, [87] with the exception of L. acidophilus and L. delbrueckii , which are sensitive. [88] Other Gram-positive bacteria with intrinsic resistance to vancomycin include Erysipelothrix rhusiopathiae , Weissella confusa , and Clostridium innocuum . [89] [90] [91]

Most Gram-negative bacteria are intrinsically resistant to vancomycin because their outer membranes are impermeable to large glycopeptide molecules [92] (with the exception of some non-gonococcal Neisseria species). [93]

Acquired resistance

Evolution of microbial resistance 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 emerged in 1986. [94] Vancomycin resistance evolved in more common pathogenic organisms during the 1990s and 2000s, including vancomycin-intermediate S. aureus (VISA) and vancomycin-resistant S. aureus (VRSA). [95] [96] Agricultural use of avoparcin, another similar glycopeptide antibiotic, may have contributed to the evolution of vancomycin-resistant organisms. [97] [98] [99] [100]

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. [101]

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:

Variant of vancomycin has been tested that binds to the resistant D-lactic acid variation in vancomycin-resistant bacterial cell walls, and also binds well to the original target (vancomycin-susceptible bacteria). [102] [103]

"Re-gained" vancomycin

In 2020 a team at the University Hospital Heidelberg (Germany) re-gained the antibacterial power of vancomycin by modifying the molecule with a cationic oligopeptide. The oligopeptide consists of six arginin units in Position VN. In comparison to the unmodified vancomycin the activity against vancomycin-resistant bacteria could be enhanced by a factor of 1,000. [104] [105] This pharmacon is still in preclinical development. Therefore, a potential approval will take several more years.

Research directions

The combination of vancomycin powder and povidone-iodine lavage has shown promise in reducing the risk of periprosthetic joint infection in hip and knee arthroplasties. In several studies, this combination was found to be more effective than vancomycin alone in preventing joint infection, with lower rates of infection and fewer adverse events. However, there is still a need for prospective randomized studies to confirm these findings and assess the long-term efficacy and safety of this treatment approach. The research directions are to determine the optimal dosage and timing of vancomycin and povidone-iodine lavage, as well as their potential synergistic effect, safety, and efficiency of this possible future treatment option in reducing the risk of periprosthetic joint infection in hip and knee arthroplasties. [106]

History

Vancomycin was first isolated in 1953, by Edmund Kornfeld (working at Eli Lilly) from a bacteria in a soil sample collected from the interior jungles of Borneo by a missionary, William M. Bouw (1918–2006). [107] The organism that produced it was eventually named Amycolatopsis orientalis . [31] The original indication for vancomycin was for the treatment of penicillin-resistant Staphylococcus aureus. [31] [32]

The compound was initially called compound 05865, but was eventually given the generic name vancomycin, derived from the term "vanquish". [31] 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 its being fast-tracked for approval by the Food and Drug Administration. In 1958, Eli Lilly first marketed vancomycin hydrochloride under the trade name Vancocin. [32]

Vancomycin never became the first-line treatment for S. aureus for several reasons:

  1. It possesses poor oral bioavailability, so must be given intravenously for most infections.
  2. β-Lactamase-resistant semisynthetic penicillins such as methicillin (and its successors, nafcillin and cloxacillin) were subsequently developed, which have better activity against non-MRSA staphylococci.
  3. Early trials used early, impure forms of the drug ("Mississippi mud"), which were found to be toxic to the inner ear and to the kidneys; [108] these findings led to vancomycin's being relegated to the position of a drug of last resort. [32]

In 2004, Eli Lilly licensed Vancocin to ViroPharma in the U.S., Flynn Pharma in the UK, and Aspen Pharmacare in Australia. The patent had expired in the early 1980s, and the FDA authorized the sale of several generic versions in the US, including from manufacturers Bioniche Pharma, Baxter Healthcare, Sandoz, Akorn-Strides, and Hospira. [109]

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Linezolid is an antibiotic used for the treatment of infections caused by Gram-positive bacteria that are resistant to other antibiotics. Linezolid is active against most Gram-positive bacteria that cause disease, including streptococci, vancomycin-resistant enterococci (VRE), and methicillin-resistant Staphylococcus aureus (MRSA). The main uses are infections of the skin and pneumonia although it may be used for a variety of other infections including drug-resistant tuberculosis. It is used either by injection into a vein or by mouth.

<span class="mw-page-title-main">Aminoglycoside</span> Antibacterial drug

Aminoglycoside is a medicinal and bacteriologic category of traditional Gram-negative antibacterial medications that inhibit protein synthesis and contain as a portion of the molecule an amino-modified glycoside (sugar). The term can also refer more generally to any organic molecule that contains amino sugar substructures. Aminoglycoside antibiotics display bactericidal activity against Gram-negative aerobes and some anaerobic bacilli where resistance has not yet arisen but generally not against Gram-positive and anaerobic Gram-negative bacteria.

<span class="mw-page-title-main">Clindamycin</span> Antibiotic

Clindamycin is a lincosamide antibiotic medication used for the treatment of a number of bacterial infections, including osteomyelitis (bone) or joint infections, pelvic inflammatory disease, strep throat, pneumonia, acute otitis media, and endocarditis. It can also be used to treat acne, and some cases of methicillin-resistant Staphylococcus aureus (MRSA). In combination with quinine, it can be used to treat malaria. It is available by mouth, by injection into a vein, and as a cream or a gel to be applied to the skin or in the vagina.

<span class="mw-page-title-main">Colistin</span> Antibiotic

Colistin, also known as polymyxin E, is an antibiotic medication used as a last-resort treatment for multidrug-resistant Gram-negative infections including pneumonia. These may involve bacteria such as Pseudomonas aeruginosa, Klebsiella pneumoniae, or Acinetobacter. It comes in two forms: colistimethate sodium can be injected into a vein, injected into a muscle, or inhaled, and colistin sulfate is mainly applied to the skin or taken by mouth. Colistimethate sodium is a prodrug; it is produced by the reaction of colistin with formaldehyde and sodium bisulfite, which leads to the addition of a sulfomethyl group to the primary amines of colistin. Colistimethate sodium is less toxic than colistin when administered parenterally. In aqueous solutions it undergoes hydrolysis to form a complex mixture of partially sulfomethylated derivatives, as well as colistin. Resistance to colistin began to appear as of 2015.

<span class="mw-page-title-main">Teicoplanin</span> Pharmaceutical drug

Teicoplanin is an semisynthetic glycopeptide antibiotic with a spectrum of activity similar to vancomycin. Its mechanism of action is to inhibit bacterial cell wall peptidoglycan synthesis. It is used in the prophylaxis and treatment of serious infections caused by Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus and Enterococcus faecalis.

Vancomycin-resistant <i>Staphylococcus aureus</i> Antibiotica resistant bacteria

Vancomycin-resistant Staphylococcus aureus (VRSA) are strains of Staphylococcus aureus that have acquired resistance to the glycopeptide antibiotic vancomycin. Bacteria can acquire resistant genes either by random mutation or through the transfer of DNA from one bacterium to another. Resistance genes interfere with the normal antibiotic function and allow a bacteria to grow in the presence of the antibiotic. Resistance in VRSA is conferred by the plasmid-mediated vanA gene and operon. Although VRSA infections are uncommon, VRSA is often resistant to other types of antibiotics and a potential threat to public health because treatment options are limited. VRSA is resistant to many of the standard drugs used to treat S. aureus infections. Furthermore, resistance can be transferred from one bacterium to another.

Multiple drug resistance (MDR), multidrug resistance or multiresistance is antimicrobial resistance shown by a species of microorganism to at least one antimicrobial drug in three or more antimicrobial categories. Antimicrobial categories are classifications of antimicrobial agents based on their mode of action and specific to target organisms. The MDR types most threatening to public health are MDR bacteria that resist multiple antibiotics; other types include MDR viruses, parasites.

<span class="mw-page-title-main">Glycopeptide antibiotic</span> Class of antibiotic drugs

Glycopeptide antibiotics are a class of drugs of microbial origin that are composed of glycosylated cyclic or polycyclic nonribosomal peptides. Significant glycopeptide antibiotics include the anti-infective antibiotics vancomycin, teicoplanin, telavancin, ramoplanin and decaplanin, corbomycin, complestatin and the antitumor antibiotic bleomycin. Vancomycin is used if infection with methicillin-resistant Staphylococcus aureus (MRSA) is suspected.

<span class="mw-page-title-main">Piperacillin</span> Antibiotic medication

Piperacillin is a broad-spectrum β-lactam antibiotic of the ureidopenicillin class. The chemical structure of piperacillin and other ureidopenicillins incorporates a polar side chain that enhances penetration into Gram-negative bacteria and reduces susceptibility to cleavage by Gram-negative beta lactamase enzymes. These properties confer activity against the important hospital pathogen Pseudomonas aeruginosa. Thus piperacillin is sometimes referred to as an "anti-pseudomonal penicillin".

<span class="mw-page-title-main">Tigecycline</span> Chemical compound

Tigecycline, sold under the brand name Tygacil, is a tetracycline antibiotic medication for a number of bacterial infections. It is a glycylcycline administered intravenously. It was developed in response to the growing rate of antibiotic resistant bacteria such as Staphylococcus aureus, Acinetobacter baumannii, and E. coli. As a tetracycline derivative antibiotic, its structural modifications has expanded its therapeutic activity to include Gram-positive and Gram-negative organisms, including those of multi-drug resistance.

Vancomycin-resistant <i>Enterococcus</i> Bacterial strains of Enterococcus that are resistant to the antibiotic vancomycin

Vancomycin-resistant Enterococcus, or vancomycin-resistant enterococci (VRE), are bacterial strains of the genus Enterococcus that are resistant to the antibiotic vancomycin.

A drug of last resort (DoLR), also known as a heroic dose, is a pharmaceutical drug which is tried after all other drug options have failed to produce an adequate response in the patient. Drug resistance, such as antimicrobial resistance or antineoplastic resistance, may make the first-line drug ineffective, especially in case of multidrug-resistant pathogens and tumors. Such an alternative may be outside of extant regulatory requirements or medical best practices, in which case it may be viewed as salvage therapy.

<span class="mw-page-title-main">Oritavancin</span> Pharmaceutical drug

Oritavancin, sold under the brand name Orbactiv among others, is a semisynthetic glycopeptide antibiotic medication for the treatment of serious Gram-positive bacterial infections. Its chemical structure as a lipoglycopeptide is similar to vancomycin.

<span class="mw-page-title-main">Dalbavancin</span> Antibiotic used to treat MRSA

Dalbavancin, sold under the brand names Dalvance in the US and Xydalba in the EU among others, is a second-generation lipoglycopeptide antibiotic medication. It belongs to the same class as vancomycin, the most widely used and one of the treatments available to people infected with methicillin-resistant Staphylococcus aureus (MRSA).

<span class="mw-page-title-main">Arbekacin</span> Antibiotic

Arbekacin (INN) is a semisynthetic aminoglycoside antibiotic which was derived from kanamycin. It is primarily used for the treatment of infections caused by multi-resistant bacteria including methicillin-resistant Staphylococcus aureus (MRSA). Arbekacin was originally synthesized from dibekacin in 1973 by Hamao Umezawa and collaborators. It has been registered and marketed in Japan since 1990 under the trade name Habekacin. Arbekacin is no longer covered by patent and generic versions of the drug are also available under such trade names as Decontasin and Blubatosine.

ESKAPE is an acronym comprising the scientific names of six highly virulent and antibiotic resistant bacterial pathogens including: Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter spp. The acronym is sometimes extended to ESKAPEE to include Escherichia coli. This group of Gram-positive and Gram-negative bacteria can evade or 'escape' commonly used antibiotics due to their increasing multi-drug resistance (MDR). As a result, throughout the world, they are the major cause of life-threatening nosocomial or hospital-acquired infections in immunocompromised and critically ill patients who are most at risk. P. aeruginosa and S. aureus are some of the most ubiquitous pathogens in biofilms found in healthcare. P. aeruginosa is a Gram-negative, rod-shaped bacterium, commonly found in the gut flora, soil, and water that can be spread directly or indirectly to patients in healthcare settings. The pathogen can also be spread in other locations through contamination, including surfaces, equipment, and hands. The opportunistic pathogen can cause hospitalized patients to have infections in the lungs, blood, urinary tract, and in other body regions after surgery. S. aureus is a Gram-positive, cocci-shaped bacterium, residing in the environment and on the skin and nose of many healthy individuals. The bacterium can cause skin and bone infections, pneumonia, and other types of potentially serious infections if it enters the body. S. aureus has also gained resistance to many antibiotic treatments, making healing difficult. Because of natural and unnatural selective pressures and factors, antibiotic resistance in bacteria usually emerges through genetic mutation or acquires antibiotic-resistant genes (ARGs) through horizontal gene transfer - a genetic exchange process by which antibiotic resistance can spread.

Kerry L. LaPlante is an American pharmacist, academic and researcher. She is the Dean at the University of Rhode Island College of Pharmacy. She is a Professor of Pharmacy and former department Chair of the Department of Pharmacy Practice at the University of Rhode Island, an Adjunct Professor of Medicine at Brown University, an Infectious Diseases Pharmacotherapy Specialist, and the Director of the Rhode Island Infectious Diseases Fellowship and Research Programs at the Veterans Affairs Medical Center in Providence, Rhode Island.

<span class="mw-page-title-main">Ototoxic medication</span>

Ototoxicity is defined as the toxic effect on the functioning of the inner ear, which may lead to temporary or permanent hearing loss (cochleotoxic) and balancing problems (vestibulotoxic). Drugs or pharmaceutical agents inducing ototoxicity are regarded as ototoxic medications.

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