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Crystal structure of a short peptide L-Lys-D-Ala-D-Ala (bacterial cell wall precursor, in green) bound to vancomycin (blue) through hydrogen bonds. Reported by Knox and Pratt in Antimicrob. Agents. Chemother., 1990 1342-1347

Vancomycin INN /væŋkɵˈmaɪsɨn/ is a glycopeptide antibiotic used in the prophylaxis and treatment of infections caused by Gram-positive bacteria. Vancomycin was first isolated in 1953 at Eli Lilly, from a soil sample collected from the interior jungles of Borneo by a missionary. It is a naturally occurring antibiotic made by the soil bacterium Actinobacteria species Amycolatopsis orientalis (formerly designated Nocardia orientalis). It is a complex chemical compound and an example of a comparatively rare haloorganic natural compound, containing two covalently bonded chlorine atoms.

The compound was industrially produced by fermentation and given the generic name vancomycin, derived from the term "vanquish." The original indication for vancomycin was for the treatment of penicillin-resistant Staphylococcus aureus, a use kept alive for many years by the fact that compound had to be given intravenously and thus provided bacteria fewer opportunities to evolve resistance, and the fact that organisms were relatively slow to evolve to adapt to it, even in experiments.

For many years since its initial use, vancomycin has traditionally been reserved as a drug of "last resort", used only after treatment with other antibiotics had failed.^[1] Recently, however, vancomycin resistant organisms are becoming common. Thus, vancomycin is increasingly being displaced from this role by newer antibiotics such as linezolid (Zyvox), daptomycin (Cubicin), and quinupristin/dalfopristin (Synercid).

1 History
2 Biosynthesis
3 Pharmacology and chemistry
- 3.1 Mechanism of action
4 Clinical use
- 4.1 Indications
- 4.2 Adverse effects
- 4.3 Dosing considerations
  - 4.3.1 Intravenous vs oral administration
  - 4.3.2 Red man syndrome
- 4.4 Therapeutic drug monitoring
5 Usage in plant tissue culture
6 Toxicity
- 6.1 Nephrotoxicity
- 6.2 Ototoxicity
- 6.3 Interactions with other nephrotoxins
7 Antibiotic resistance
- 7.1 Intrinsic resistance
- 7.2 Acquired resistance
8 See also
9 References

History[edit source | edit]

Vancomycin was first isolated in 1953 by Edmund Kornfeld (working at Eli Lilly) from a soil sample collected from the interior jungles of Borneo by a missionary.^[2] The organism that produced it was eventually named Amycolatopsis orientalis.^[3] The original indication for vancomycin was for the treatment of penicillin-resistant Staphylococcus aureus.^[3]^[4]

The compound was initially called compound 05865, but was eventually given the generic name vancomycin, derived from the term "vanquish".^[3] 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 Food and Drug Administration (FDA) in 1958. Eli Lilly first marketed vancomycin hydrochloride under the trade name Vancocin^[4] and as COVANC from Nucleus, India.^{[citation needed]}

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 methicillin (and its successors, nafcillin and cloxacillin) 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;^[5] these findings led to vancomycin's being relegated to the position of a drug of last resort.^[4]

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 authorized the sale of several generic versions in the USA, including from manufacturers Bioniche Pharma, Baxter Healthcare, Sandoz, Akorn Strides and Hospira.^[6]

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. difficile. This product is currently marketed by ViroPharma in the USA.^[7]

Biosynthesis[edit source | edit]

Figure 1: Modules and Domains of Vancomycin assembly.

Vancomycin biosynthesis occurs via different nonribosomal protein synthases (NRPSs).^[8] 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).^[9]

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

Nonribosomal peptide synthesis occurs through distinct modules that can load and extend the protein by one amino acid through the amide bond formation at the contact sites of the activating domains.^[10] 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^[11]^[12] 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.^[13] 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.

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

A set of multienzymes (peptide synthase CepA, CepB, and CepC) are responsible for assembling the heptapeptide. (Figure 2). The organization of CepA, CepB, and Cep C closely resembles other peptide synthases such as those for surfactin (SrfA1, SrfA2, and SrfA3) and gramicidin (GrsA and GrsB).^[10] 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.^[10]

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, in order to become biologically active (Figure 3). To convert the linear heptapeptide, eight enzymes, open reading frames (ORF) 7, 8, 9, 10, 11, 14, 18, 20, and 21 are used. The enzymes ORF 7, 8, 9, and 20 are P450 enzymes. ORF 10 and 18 show to nonheme haloperoxidases^{[clarification needed]}. And ORF 9 and 14 are identified as putative hydroxylation enzymes.^[14] 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.^[10]

Pharmacology and chemistry[edit source | edit]

Vancomycin is a branched tricyclic glycosylated nonribosomal peptide produced by the Actinobacteria 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]} and, therefore,^{[citation needed]} has more potent activity.

Mechanism of action[edit source | edit]

Vancomycin acts by inhibiting proper cell wall 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.^[15]

Mechanism of vancomycin action and resistance. Note that 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.

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.
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.
In resistant bacteria, cross-links are successfully formed. However, in the non-resistant bacteria, the vancomycin bound to the peptide chains prevents them from interacting properly with the cell wall cross-linking enzyme.
In the resistant bacteria, stable cross links are formed. In the sensitive bacteria, cross-links cannot be formed and the cell wall falls apart.

Clinical use[edit source | edit]

Indications[edit source | edit]

Vancomycin is indicated for the treatment of serious, life-threatening infections by Gram-positive 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.^[16]^[17]

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:^[18]^[19]

Treatment of serious infections caused by susceptible organisms resistant to penicillins (methicillin-resistant Staphylococcus aureus and multi-resistant Staphylococcus epidermidis (MRSE)) or in individuals with serious allergy to penicillins
Treatment of Pseudomembranous colitis caused by the bacterium Clostridium difficile; in particular, in cases of relapse or where the infection is unresponsive to metronidazole 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.^[19]
Antibacterial prophylaxis for endocarditis following certain procedures in penicillin-hypersensitive individuals at high risk^[19]
Surgical prophylaxis for major procedures involving implantation of prostheses in institutions with a high rate of MRSA or MRSE^[19]
Early in treatment as an empiric antibiotic for possible MRSA infection while waiting for culture identification of the infecting organism.

Adverse effects[edit source | edit]

Although vancomycin levels are usually monitored, in an effort to reduce adverse events, the value of this is not beyond debate.^[20] 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.^[21]

Common adverse drug reactions (≥1% of patients) associated with IV vancomycin include: local pain, which may be severe and/or thrombophlebitis.

Damage to the kidneys and to the hearing were a side-effect of the early impure versions of vancomycin, and these were prominent in the clinical trials conducted in the mid-1950s.^[3]^[4] Later trials using purer forms of vancomycin found that nephrotoxicity is an infrequent adverse effect (0.1–1% of patients), but that this is accentuated in the presence of aminoglycosides.^[22]

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).^[18]

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.^[23]

Dosing considerations[edit source | edit]

Intravenous vs oral administration[edit source | edit]

Vancomycin must be given intravenously (IV) for systemic therapy, since it is not 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.^[24]

The only indication for oral vancomycin therapy is in the treatment of pseudomembranous colitis, where it must be given orally to reach the site of infection in the colon. Following oral administration, the fecal concentration of vancomycin is around 500 µg/mL^[25] (sensitive strains of C. difficile have a mean inhibitory concentration of ≤2 µg/mL^[26])

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.^[27]

Red man syndrome[edit source | edit]

Therapeutic drug monitoring[edit source | edit]

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 (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.^[18]^[30]^[31]^[32]

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,^[33] 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.^[34]^[35]

Usage in plant tissue culture[edit source | edit]

Vancomycin is one of the few antibiotics used in plant tissue culture to eliminate Gram-positive bacteria infection. It has relatively low toxicity to plants.^[36]

Toxicity[edit source | edit]

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.^[3]

Nephrotoxicity[edit source | edit]

Subsequent reviews of accumulated case reports of vancomycin-related nephrotoxicity 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.^[30] 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.

Ototoxicity[edit source | edit]

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

Interactions with other nephrotoxins[edit source | edit]

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

Antibiotic resistance[edit source | edit]

Intrinsic resistance[edit source | edit]

There are a few Gram-positive bacteria that are intrinsically resistant to vancomycin: Leuconostoc and Pediococcus species, but these organisms are rare causes of disease in humans.^[37] Most Lactobacillus species are also intrinsically resistant to vancomycin^[37] (the exception is the finding of a few strains (but not all) of L. acidophilus^[38]). Other Gram-positive bacteria with intrinsic resistance to vancomycin include Erysipelothrix rhusiopathiae, Weissella confusa, and Clostridium innocuum.^[39]^[40]^[41]

Most Gram-negative bacteria are intrinsically resistant to vancomycin because their outer membrane is impermeable to large glycopeptide molecules^[42] (with the exception of some non-gonococcal Neisseria species).^[43]

Acquired resistance[edit source | edit]

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 (VRE) emerged in 1987. Vancomycin resistance evolved in more common pathogenic organisms during the 1990s and 2000s, including vancomycin-intermediate Staphylococcus aureus (VISA) and vancomycin-resistant Staphylococcus aureus (VRSA).^[44]^[45] There is some suspicion that agricultural use of avoparcin, another similar glycopeptide antibiotic, has contributed to the evolution of vancomycin-resistant organisms.^[46]^[47]^[48]^[49]

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.^[50]

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 teicoplanin; inducible on exposure to these agents
VanB - lower-level resistance; inducible by vancomycin, but strains may remain susceptible to teicoplanin
VanC - least clinically important; resistance only to vancomycin; constitutive resistance

2011: A variant of vancomycin was tested that binds to the lactate variation and also binds well to the original target, thus reinstates potent antimicrobial activity.^[51]

References[edit source | edit]

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^ McDonald, LC; Killgore, GE; Thompson, A; Owens Jr, RC; Kazakova, SV; Sambol, SP; Johnson, S; Gerding, DN (December 2005). "An epidemic, toxin gene-variant strain of Clostridium difficile" (PDF). The New England Journal of Medicine 353 (23): 2433–41. doi:10.1056/NEJMoa051590. PMID 16322603.
^ Acar, J.; Casewell, M.; Freeman, J.; Friis, C.; Goossens, H. (2000). "Avoparcin and virginiamycin as animal growth promoters: A plea for science in decision-making". Clinical Microbiology and Infection 6 (9): 477–82. doi:10.1046/j.1469-0691.2000.00128.x. PMID 11168181.
^ Bager, F; Madsen, M; Christensen, J; Aarestrup, F.M (1997). "Avoparcin used as a growth promoter is associated with the occurrence of vancomycin-resistant Enterococcus faecium on Danish poultry and pig farms". Preventive Veterinary Medicine 31 (1–2): 95–112. doi:10.1016/S0167-5877(96)01119-1. PMID 9234429.
^ Peter J Collignon (1999). "Vancomycin-resistant enterococci and use of avoparcin in animal feed: is there a link?". Med J Aust 171 (3): 144–146. PMID 10474607.
^ Lauderdale, TL; Shiau, YR; Wang, HY; Lai, JF; Huang, IW; Chen, PC; Chen, HY; Lai, SS et al. (2007). "Effect of banning vancomycin analogue avoparcin on vancomycin-resistant enterococci in chicken farms in Taiwan". Environmental microbiology 9 (3): 819–23. doi:10.1111/j.1462-2920.2006.01189.x. PMID 17298380. |displayauthors= suggested (help)
^ Pootoolal J, Neu J, Wright GD (2002). "Glycopeptide antibiotic resistance". Annu Rev Pharmacol Toxicol 42: 381–408. doi:10.1146/annurev.pharmtox.42.091601.142813. PMID 11807177.
^ Xie, J; Pierce, JG; James, RC; Okano, A; Boger, DL (September 2011). "A Redesigned Vancomycin Engineered for Dual d-Ala-d-Ala and d-Ala-d-Lac Binding Exhibits Potent Antimicrobial Activity Against Vancomycin-Resistant Bacteria". J. Am. Chem. Soc. 133 (35): 13946–9. doi:10.1021/ja207142h. PMC 3164945. PMID 21823662.

UpToDate Contents

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1. バンコマイシン過敏症 vancomycin hypersensitivity
2. 成人におけるバンコマイシン投与および血清濃度のモニタリング vancomycin dosing and serum concentration monitoring in adults
3. バンコマイシン中等度耐性およびバンコマイシン耐性黄色ブドウ球菌感染症 vancomycin intermediate and vancomycin resistant staphylococcus aureus infections
4. バンコマイシン耐性腸球菌の疫学、予防および管理 epidemiology prevention and control of vancomycin resistant enterococci
5. コアグラーゼ陰性ブドウ球菌による感染症の治療 treatment of infections due to coagulase negative staphylococci

English Journal

Microparticles based on chitosan/carboxymethylcellulose polyelectrolyte complexes for colon delivery of vancomycin.

Cerchiara T1, Abruzzo A2, Parolin C2, Vitali B2, Bigucci F2, Gallucci MC3, Nicoletta FP4, Luppi B2.
Carbohydrate polymers.Carbohydr Polym.2016 Jun 5;143:124-30. doi: 10.1016/j.carbpol.2016.02.020. Epub 2016 Feb 9.
The aim of this work was to prepare polyelectrolyte complexes based on chitosan (CH) and carboxymethylcellulose (CMC) for colon delivery of vancomycin (VM). Various batches of polyelectrolyte complexes, using three different CH/CMC weight ratios (3:1, 1:1 and 1:3), were prepared and collected as mic
PMID 27083351

Comparing the ocular surface effects of topical vancomycin and linezolid for treating bacterial keratitis.

Akova Budak B1, Baykara M1, Kıvanç SA1, Yilmaz H1, Cicek S1.
Cutaneous and ocular toxicology.Cutan Ocul Toxicol.2016 Jun;35(2):126-30. doi: 10.3109/15569527.2015.1058273. Epub 2015 Jun 23.
BACKGROUND: Vancomycin is the gold standard in combination therapy for severe and resistant gram-positive keratitis and in particular for Methicillin-resistant Staphylococcus aureus (MRSA) infections. The aim of this study was to report the ocular surface toxicity and scoring in patients whose treat
PMID 26100380

Polyelectrolyte complex of vancomycin as a nanoantibiotic: Preparation, in vitro and in silico studies.

Sikwal DR1, Kalhapure RS1, Rambharose S1, Vepuri S1, Soliman M1, Mocktar C1, Govender T2.
Materials science & engineering. C, Materials for biological applications.Mater Sci Eng C Mater Biol Appl.2016 Jun 1;63:489-98. doi: 10.1016/j.msec.2016.03.019. Epub 2016 Mar 9.
Delivery of antibiotics by various nanosized carriers is proving to be a promising strategy to combat limitations associated with conventional dosage forms and the ever-increasing drug resistance problem. This method entails improving the pharmacokinetic parameters for accumulation at the target inf
PMID 27040243

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「バンコマイシン」

Vancomycin
Systematic (IUPAC) name
	(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
Clinical data
Trade names	Vancocin
AHFS/Drugs.com	monograph
MedlinePlus	a604038
Licence data	US FDA:link
Pregnancy cat.	B2 (Au), B (PO) / C (IV)(U.S.)
Legal status	Prescription Only (S4) (AU) POM (UK) ℞-only (US)
Routes	IV, oral
Pharmacokinetic data
Bioavailability	Negligible (oral)
Metabolism	Excreted unchanged
Half-life	4–11 hours (adults); 6-10 days (adults, impaired renal function)
Excretion	Renal
Identifiers
CAS number	1404-90-6
ATC code	A07AA09 J01XA01
PubChem	CID 14969
DrugBank	DB00512
ChemSpider	14253
UNII	6Q205EH1VU
KEGG	D00212
ChEBI	CHEBI:28001
ChEMBL	CHEMBL262777
Chemical data
Formula	C66H75Cl2N9O24
Mol. mass	1449.3 g.mol-1
	SMILES 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 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 ; Key:MYPYJXKWCTUITO-LYRMYLQWSA-N ;
(what is this?) (verify);

　　[★]

英: vancomycin, VCM
化: 塩酸バンコマイシン vancomycin hydrochloride
商: Vancocin, Luphocin、バンマイシン
関: 抗菌薬一覧、テイコプラニン、メトロニダゾール

first aid step1 2006 p.140,165,166,169,173,207

抗菌薬

グリコペプチド系抗生物質

特徴

Streptomyces orientalisから分離
経腸管的に吸収されないため骨髄移植時の消化管内消毒に用いられる。

構造

作用機序

細胞壁合成阻害作用(block peptidoglycan synthesis)
細胞内で作られたmurein monomerの重合を妨げる？

薬理作用

抗菌スペクトル

MRSAを含むほとんどのグラム陽性菌と一部の嫌気性菌に抗菌作用を示す
殺菌的に作用(bactericidal antibiotics)

動態

腸管からほとんど吸収されない→腸管殺菌のための経口投与、点滴静注による全身投与で用いられる

適応

感染性腸炎
骨髄移植時の消化管内殺菌

[US?]MRSA(methicillin-resistant Staphylococcus aureus), penicillin-resistant Sreptococcus pneumoniae

適応菌種

メチシリン耐性黄色ブドウ球菌、クロストリジウム・ディフィシル

注意

禁忌

副作用

nephrotoxicity, ototoxicity, thrombophlebitis, diffuse flushing(red man syndrome) (first aid step1 2006 p.169)

重大な副作用

添付文書

1)ショック：0.1%未満(血圧低下、不快感、口内異常感、喘鳴、眩暈、便意、耳鳴り、発汗等)
2)注射用塩酸バンコマイシン製剤：アナフィラキシー様症状、急性腎不全、間質性腎炎、汎血球減少、無顆粒球症、血小板減少、皮膚粘膜眼症候群(Stevens-Johnson症候群)、中毒性表皮壊死症(Lyell症候群)、剥脱性皮膚炎、第8脳神経障害、偽膜性大腸炎、肝機能障害、黄疸

その他

1)過敏症(発熱、発疹、潮紅、悪寒、蕁麻疹、そう痒)
2)血液(好酸球増多、白血球減少、血小板減少)
3)肝臓(AST・ALT・Al-P上昇)
4)消化器(下痢：48%、悪心：28%、嘔吐：34%、食欲不振)　←骨髄移植時の消化管内殺菌における発現頻度
5)腎臓(BUN・クレアチニンの上昇)
6)その他(口内炎、舌炎)

[1] "Lifeline for 'antibiotic of last resort': Mechanism that triggers resistance to vancomycin identified".

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[6] Orange Book: Approved Drug Products with Therapeutic Equivalence Evaluations

[7] Orange Book Detail Record Search

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[15] Clinical Pharmacology

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[17] Gonzalez C, Rubio M, Romero-Vivas J, Gonzalez M, Picazo JJ (1999). "Bacteremic pneumonia due to Staphylococcus aureus: a comparison of disease caused by methicillin-resistant and methicillin-susceptible organisms". Clin Infect Dis 29 (5): 1171–7. doi:10.1086/313440. PMID 10524959.

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[21] Lodise TP, Patel N, Lomaestro BM, Rodvold KA, Drusano GL (2009). "Relationship between initial vancomycin concentration‐time profile and nephrotoxicity among hospitalized patients". Clin Infect Dis 49 (4): 507–514. doi:10.1086/600884. PMID 19586413.

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[26] Peláez T, Alcalá L, Alonso R, et al. (2002). "Reassessment of Clostridium difficile susceptibility to metronidazole and vancomycin". Antimicrob Agents Chemother 46 (6): 1647–1650. doi:10.1128/AAC.46.6.1647-1650.2002.

[27] Choosing the Right Intravenous Catheter

[Sivagnanam2003-28] Sivagnanam, S; Deleu, D (2003). "Red man syndrome". Critical care (London, England) 7 (2): 119–20. doi:10.1186/cc1871. PMC 270616. PMID 12720556.

[Andrews-29] James, William; Berger, Timothy; Elston, Dirk (2005). Andrews' Diseases of the Skin: Clinical Dermatology. (10th ed.). Saunders. ISBN 0-7216-2921-0.

[Cantu1994-30] Cantú, TG; Yamanaka-Yuen, NA; Lietman, PS (1994). "Serum vancomycin concentrations: reappraisal of their clinical value". Clinical Infectious Diseases 18 (4): 533–43. doi:10.1093/clinids/18.4.533. PMID 8038306.

[Moellering1994-31] Moellering Jr, RC (1994). "Monitoring serum vancomycin levels: climbing the mountain because it is there?". Clinical Infectious Diseases 18 (4): 544–6. doi:10.1093/clinids/18.4.544. PMID 8038307.

[Karam1999-32] Karam, CM; McKinnon, PS; Neuhauser, MM; Rybak, MJ (1999). "Outcome assessment of minimizing vancomycin monitoring and dosing adjustments". Pharmacotherapy 19 (3): 257–66. doi:10.1592/phco.19.4.257.30933. PMID 10221365.

[33] Geraci J (1977). "Vancomycin". Mayo Clin Proc 52 (10): 631–4. PMID 909314.

[34] Rybak M, Lomaestro B, Rotschafer JC, et al. (2009). "Therapeutic monitoring of vancomycin in adult patients: A consensus review of the American Society of Health-System Pharmacists, the Infectious Diseases Society of America, and the Society of Infectious Diseases Pharmacists". American Journal of Health-System Pharmacy 66 (1): 82–98. doi:10.2146/ajhp080434. PMID 19106348.

[35] Thomson AH, Staatz CE, Tobin CM, Gall M, Lovering AM. Development and evaluation of vancomycin dosage guidelines designed to achieve new target concentrations. J. Antimicrob. Chemother. 63: 1050-1057, 2009.

[Vancomcyin_for_plant_tissue_culture-36] vancomcin for plant cell culture

[Swenson1990-37] Swenson JM, Facklam RR, Thornsberry C (April 1990). "Antimicrobial susceptibility of vancomycin-resistant Leuconostoc, Pediococcus, and Lactobacillus species". Antimicrob Agents Chemother 34 (4): 543–9. doi:10.1128/AAC.34.4.543. PMC 171641. PMID 2344161.

[38] Hamilton-Miller JM, Shah S (February 1998). "Vancomycin susceptibility as an aid to the identification of lactobacilli". Lett Appl Microbiol 26 (2): 153–4. doi:10.1046/j.1472-765X.1998.00297.x. PMID 9569701.

[39] Romney, M; Cheung, S; Montessori, V (2001). "Erysipelothrix rhusiopathiae endocarditis and presumed osteomyelitis". The Canadian Journal of Infectious Diseases 12 (4): 254–256. PMC 2094827. PMID 18159347.

[40] ttp://www.ncbi.nlm.nih.gov/pubmed/15150227

[41] ttp://jmm.sgmjournals.org/content/early/2011/05/19/jmm.0.027169-0

[42] Quintiliani R Jr, Courvalin P (1995). "Mechanisms of Resistance to Antimicrobial Agents". In Murray PR, Baron EJ, Pfaller MA, Tenover FC, Yolken RH. Manual of Clinical Microbiology (6th ed.). Washington DC: ASM Press. p. 1319. ISBN 1-55581-086-1.

[43] Geraci JE, Wilson WR (1981). "Vancomycin therapy for infective enocarditis". Rev Infect Dis. 3 suppl: S250–8. PMID 7342289.

[Smith1999-44] Smith, TL; Pearson, ML; Wilcox, KR; Cruz, C; Lancaster, MV; Robinson-Dunn, B; Tenover, FC; Zervos, MJ et al. (February 1999). "Emergence of vancomycin resistance in Staphylococcus aureus. Glycopeptide-Intermediate Staphylococcus aureus Working Group" (PDF). The New England Journal of Medicine 340 (7): 493–501. doi:10.1056/NEJM199902183400701. PMID 10021469. |displayauthors= suggested (help)

[McDonald2005-45] McDonald, LC; Killgore, GE; Thompson, A; Owens Jr, RC; Kazakova, SV; Sambol, SP; Johnson, S; Gerding, DN (December 2005). "An epidemic, toxin gene-variant strain of Clostridium difficile" (PDF). The New England Journal of Medicine 353 (23): 2433–41. doi:10.1056/NEJMoa051590. PMID 16322603.

[46] Acar, J.; Casewell, M.; Freeman, J.; Friis, C.; Goossens, H. (2000). "Avoparcin and virginiamycin as animal growth promoters: A plea for science in decision-making". Clinical Microbiology and Infection 6 (9): 477–82. doi:10.1046/j.1469-0691.2000.00128.x. PMID 11168181.

[47] Bager, F; Madsen, M; Christensen, J; Aarestrup, F.M (1997). "Avoparcin used as a growth promoter is associated with the occurrence of vancomycin-resistant Enterococcus faecium on Danish poultry and pig farms". Preventive Veterinary Medicine 31 (1–2): 95–112. doi:10.1016/S0167-5877(96)01119-1. PMID 9234429.

[48] Peter J Collignon (1999). "Vancomycin-resistant enterococci and use of avoparcin in animal feed: is there a link?". Med J Aust 171 (3): 144–146. PMID 10474607.

[49] Lauderdale, TL; Shiau, YR; Wang, HY; Lai, JF; Huang, IW; Chen, PC; Chen, HY; Lai, SS et al. (2007). "Effect of banning vancomycin analogue avoparcin on vancomycin-resistant enterococci in chicken farms in Taiwan". Environmental microbiology 9 (3): 819–23. doi:10.1111/j.1462-2920.2006.01189.x. PMID 17298380. |displayauthors= suggested (help)

[50] Pootoolal J, Neu J, Wright GD (2002). "Glycopeptide antibiotic resistance". Annu Rev Pharmacol Toxicol 42: 381–408. doi:10.1146/annurev.pharmtox.42.091601.142813. PMID 11807177.

[51] Xie, J; Pierce, JG; James, RC; Okano, A; Boger, DL (September 2011). "A Redesigned Vancomycin Engineered for Dual d-Ala-d-Ala and d-Ala-d-Lac Binding Exhibits Potent Antimicrobial Activity Against Vancomycin-Resistant Bacteria". J. Am. Chem. Soc. 133 (35): 13946–9. doi:10.1021/ja207142h. PMC 3164945. PMID 21823662.

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案内

Vancocin